RxPG News : Therapy

Taccalonolides from bat plants selectively kill cancer cells

Tue, 22 Nov 2011 18:29:24 PST

( from http://www.rxpgnews.com ) In a new study published this month in the Journal of the American Chemical Society, researchers with The University of Texas Health Science Center at San Antonio have pinpointed the cancer-fighting potential in the bat plant, or Tacca chantrieri.

Susan Mooberry, Ph.D., leader of the Experimental Development Therapeutics Program at the Cancer Therapy & Research Center and a professor of pharmacology in the School of Medicine at the UT Health Science Center, has been working to isolate substances in the plant, looking for a plant-derived cancer drug with the potential of Taxol.

Taxol, the first microtubule stabilizer derived from the Yew family, has been an effective chemotherapy drug, but patients eventually develop problems with resistance over time and toxicity at higher doses. Researchers have long been seeking alternatives.

“We’ve been working with these for years with some good results, but never with the potency of Taxol,” said Dr. Mooberry, lead author of the study. “Now we have that potency, and we also show for the first time the taccalonolides’ cellular binding site.”

Microtubules are structures in the cells that act as conveyer belts. They help maintain cell shape and help guide chromosones in cell division to ensure that every new cell, including every new cancer cell, gets a full complement of genetic material. When microtubules are stabilized — essentially held still so they can’t do their jobs — this disrupts numerous cellular processes, and the cell can die.

The taccalonolides stabilize microtubules in cancer cells, but they do not attack healthy cells, Dr. Mooberry said. “We’ve run normal prostate cells and normal breast cells through these tests, and they don’t die. The taccalonolides selectively kill cancer cells.”

Until now, how they did this was unknown. The isolation of these highly potent taccalonolides for the first time by Dr. Mooberry’s team shows how they interact directly with microtubules.

Photodynamic therapy can help preserve the voice for patients with early stage laryngeal cancer

Sat, 29 Jan 2011 22:05:10 PST

( from http://www.rxpgnews.com ) Light, or photodynamic, therapy can help preserve the voice and vocal cord function for patients with early stage laryngeal (voice box) cancer, according to a study from Henry Ford Hospital in Detroit.

"Photodynamic therapy is an effective treatment for early laryngeal squamous cell carcinomas, offering patients a less invasive option with fewer side effects than other therapies, while preserving the voice," says study co-author Vanessa G. Schweitzer, FACS, M.D., a senior staff physician in the Department of Otolaryngology-Head & Neck Surgery at Henry Ford.

Each year in the United States, more than 10,000 people are diagnosed with laryngeal cancer. Those who smoke and drink alcohol are at a greater risk, according to the National Cancer Institute. Laryngeal cancer is most commonly treated with radiation therapy alone or in combination with surgery or chemotherapy.

But photodynamic therapy offers some patients another option.

"It is a good alternative to radiation and surgery for early staged lesions. It can preserve function and allow us to reserve use of radiation therapy and surgery – both known to have more functional impairment on vocal cord function – should the cancer recur following photodynamic therapy," says study lead author Melissa L. Somers, M.D., with the Department of Otolaryngology-Head and Neck Surgery at Henry Ford.

Having already performed more than 200 procedures – more than any other hospital in Michigan – Henry Ford physicians are center stage in the application and research for this procedure.

Photodynamic therapy works by destroying deadly cancer cells without harming surrounding healthy tissue. It uses a powerful laser and a nontoxic, light-activated drug called PHOTOFRIN. The laser activates the drug, causing a reaction in the cancer cells and destroying them.

Since photodynamic therapy does not damage the underlying tissue, it not only allows for multiple treatments but also for it to be given prior to or following other therapies, and when radiation therapy fails.

However, there is not a consensus in research literature as to which treatment – surgery, radiation therapy or photodynamic therapy – produces the best outcome for voice preservation.

The current Henry Ford study focuses on 10 patients with early stage squamous cell tumors of the larynx treated with photodynamic therapy. The study assessed how well the vocal cords moved following photodynamic therapy.

Both before and after photodynamic therapy, patients underwent videostroboscopy exams, a state-of-the-art technique that provides a magnified, slow-motion view of the vocal cords in use. The technique uses a small, angled telescope inserted through the mouth or nose to measure vocal cord vibrations while patients repeat words or sounds.

Results were analyzed by a speech language pathologist and laryngologist specializing in voice disorders for vocal cord movement and vibration.

During the first five weeks following treatment, researchers noted a significant worsening in the non-vibrating portion of the affected vocal cords, which is expected, says Dr. Somers.

Ten weeks following treatment, there was a noticeable improvement.

"In our study, patients undergoing PDT demonstrated initial significant impairment in the vocal cord vibratory parameters of mucosal wave, non-vibrating vocal cold and amplitude of vibration as well as appearance of vocal cold edge for both the tumor and non-tumor side," says Dr. Somers. "Most notably, over the course of a few weeks and months, there were consistent trends toward normal vocal cord vibration."

Patients do experience minor side effects from treatment such as photosensitivity, making them more sensitive to light and susceptible to severe sunburns. This lasts for about four weeks following the procedure. Patients also may experience temporary hoarseness.

Dr. Somers hopes future studies are aimed at a prospective comparison of photodynamic therapy to surgery and radiation and subsequent voice production results.

Bionic Nose to Detect Cancers

Tue, 31 Mar 2009 12:12:47 PST

( from http://www.rxpgnews.com ) Washington, March 31 - Both cancer cells and chemicals used in bombs evade detection because they are present in very small quantities. But now a new method being developed can detect them by amplifying near invisible traces of biomarkers in cancer, materials in explosives or pollutants in water.

Pioneered by Doron Shabat, a bio-organic chemist and professor at Tel Aviv University's School of Chemistry, the technology being developed aims to amplify signals millions and billions of times.

'We are developing a molecular system that amplifies certain events,' said Shabat.

'That way we'll be able to respond faster to medical, security and environmental threats. In effect, our device can amplify just about any chemical system that has a certain kind of reactivity.

'It has the potential to help doctors diagnose diseases - those with biomarkers, and enzymatic activities that are compatible with our molecular probe,' Shabat explained.

'The long list includes a few kinds of cancers, including prostate cancer. But it also has applications for testing for impurities in water. It has both biological and non-biological applications,' he was quoted as saying in a Tel Aviv University release.

Shabat's invention is a molecular sensor that acts in a solution. A chemist would add trace amounts of the test material from the field - a spoonful of contaminated drinking water, for example - into the solution and would simply see if the colour of the solution changes. If so, the targeted material - the cancer, explosive or pollutant - is present.

These findings were published in Chemical Communication.

Anti- cancer gene discovered- new strategy for treatment?

Wed, 25 Feb 2009 00:48:17 PST

( from http://www.rxpgnews.com ) Starting with the tiny fruit fly, and then moving into mouse and human patients, researchers at VIB connected to the Center for Human Genetics (K.U. Leuven) showed that the same gene suppresses cancer in all three. Reciprocally, switching off the gene leads to cancer. The scientists think there is a good chance that the gene can be switched on again with a drug. They report their findings in the reputed scientific journal PLoS Biology.

Specialized cells

All of us begin our lives as one cell, which divides into two, four, eight … into a human of a few billion cells. Almost all cells in an adult human – skin cells, liver cells, eye lens cells, nerve cells, insulin-producing cells etc – are highly specialized to perform a specific function. They are no longer capable of taking on another task: when a skin cell divides, you get more skin cells. During the growth from an embryo to an adult human, the cells become more and more specialized ("differentiated", biologists say).

Cancer cells are an exception to that rule: they are much less specialized, and feel at home in different places in the body. Researchers have long believed that cells must take the last step in their specialization to be better protected from turning into cancer cells. However, this was not proven in a living organism.

Suppressing cancer

Wouter Bossuyt from the Group of Bassem Hassan and their fellow VIB researchers at K.U.Leuven, now demonstrate with fruit flies that master control genes steering the specialization step indeed inhibit tumor formation. The specific example the VIB scientists used, are the ones biologists call the Atonal genes. These genes are very similar to each other in all species, from flies to humans.

With mice, and in collaboration with colleagues from the United States, they showed that loss of one of those genes, Atonal homolog 1 or ATOH1, causes colon cancer. The gene regulates the last step in the specialization to epithelial cell of the colon. Humans with colon cancer frequently have an inactivated ATOH1 gene, the researchers observed.

Treatment

The researchers could – in a test tube – reactivate the gene in human colon cancer cells. The tumor cells stopped growing and committed suicide. Since they were able to switch the gene on with a reasonably simple chemical, this opens possibilities to one day perhaps switch the gene back on in living patients. It will be very important in the future to study in detail how exactly ATOH1 does performs its anti-cancer job

Anthracycline induced heart damage can be reduced by prolonging infusion time

Thu, 23 Nov 2006 09:41:49 PST

( from http://www.rxpgnews.com ) Stretching out a dose of chemotherapy over six or more hours may reduce the risk of heart problems caused by certain commonly used cancer drugs, according to a new review of recent research.

Anthracycline drugs like daunorubicin and doxorubicin are used to treat many types of solid tumors and blood cancers such as leukemias in adults and children.

Anthracycline therapy can be very successful at controlling cancer, but heart damage caused by anthracycline treatment is a considerable and serious problem, said Dr. Elvira van Dalen of the Emma Childrens Hospital in the Netherlands.

She and her colleagues found that the rates of heart failure among adult patients receiving anthracycline therapy were significantly lower when the patients had an infusion of the drug that lasted six or more hours, compared to shorter infusions times.

In five studies involving 557 patients, the longer treatment cut the risk of heart failure by nearly 75 percent compared to the risk in patients who received the short treatment.

van Dalen said the prolonged dose of six hours or more might be justified if a patient is at high risk of heart damage or needs a high cumulative dose of the chemotherapy.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

In some of the studies, the prolonged dose also reduced the risk of less severe problems such as weakened heart function. Patients had the same chance of survival and tumor shrinkage whether they received the long or short therapies, the Cochrane researchers found.

It should be emphasized that the majority of the patients included in these studies were adults with advanced solid tumors, van Dalen and colleagues said, noting that there are few good studies about the length of anthracycline treatment in children.

Among the children in the study, there was no difference in heart damage between the long and short treatments and no information on survival and tumor shrinkage was available, van Dalen said.

Recent studies have shown that the toxic heart effects of anthracycline therapy can have lasting effects on childrens health. Dr. Stephen Lipshulz, a pediatric cancer specialist at the University of Miami, said childhood cancer survivors may be at significant risk of serious cardiovascular problems at a much younger age," than researchers believed a few years ago.

Lipshulzs work suggests many childhood cancer survivors suffer from enlarged hearts and prematurely hardened arteries, due at least in part from their chemotherapy. Its alarming that weve found such dramatic heart damage and blood vessel risk in some survivors who are just 10 or 15 years from treatment, he said.

Genomic signatures to guide the use of chemotherapeutics

Mon, 23 Oct 2006 18:59:00 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. Scientists at Duke University's Institute for Genome Sciences & Policy have developed a panel of genomic tests that analyzes the unique molecular traits of a cancerous tumor and determines which chemotherapy will most aggressively attack that patient's cancer.

In experiments reported in the November 2006 issue of the journal Nature Medicine, the researchers applied the genomic tests to cells derived from tumors of cancer patients. They found that the tests were 80 percent accurate in predicting which drugs would be most effective in killing the tumor.

The Duke team plans to begin a clinical trial of the genomic tests in breast cancer patients next year.

The new tests have the potential to save lives and reduce patients' exposure to the toxic side effects of chemotherapy, said Anil Potti, M.D., the study's lead investigator and an assistant professor of medicine in the Duke Institute for Genome Sciences & Policy. The tests are designed to help doctors select and initiate treatment with the best drug for a patient's tumor instead of trying various drugs in succession until the right one is found, Potti said.

"Over 400,000 patients in the United States are treated with chemotherapy each year, without a firm basis for which drug they receive," said Joseph Nevins, Ph.D., the study's senior investigator and a professor of genetics at the Duke Institute for Genome Sciences & Policy. "We believe these genomic tests have the potential to revolutionize cancer care by identifying the right drug for each individual patient."

The tests work by scanning thousands of genes from a patient's tumor to produce a "genomic" profile of the tumor's molecular makeup. Using the genomic tests in cancer cells in the laboratory, the scientists successfully matched the right chemotherapy for the patient's tumor type. The scientists were then able to validate their predictions against patients' actual clinical outcomes.

Doctors currently must use a trial-and-error approach to chemotherapy, trying various established drugs to see which has an effect. As a result, patients often undergo multiple toxic therapies in a process that places patients' lives at risk as their conditions worsen with each treatment.

"Chemotherapy will likely continue to be the backbone of many anticancer treatment strategies," said Potti. "With the new test, we think that physicians will be able to personalize chemotherapy in a way that should improve outcomes."

The first clinical trial will compare how well patients respond to chemotherapy when it is guided by the new genomic predictors versus when it is selected by physicians in the usual trial-and-error manner. The researchers anticipate that they will enroll approximately 120 patients with breast cancer in the study. Subsequent clinical trials will enroll hundreds of patients with lung and ovarian cancer, Potti said.

If proven effective, the tests could be applied to all cancers in which chemotherapy is given, not just breast, lung, and ovarian cancer, Potti said.

The researchers developed the new tests through a process that included analyzing the activity of thousands of genes in cells taken from the tumors of cancer patients.

In using the test, scientists extract the genetic molecule "messenger RNA" from a cancer patient's tumor cells. Messenger RNA translates a gene's DNA code into proteins that run the cell's activities. Hence, it is a barometer of a gene's activity level inside the cell.

The scientists then label the messenger RNA with fluorescent tags and place the labeled molecules on a tiny glass slide, called a gene chip, which binds to segments of DNA representing the tens of thousands of genes in the genome.

When scanned with special light, the fluorescent RNA emits a telltale luminescence that demonstrates how much RNA is present on the chip, and this reading indicates which genes are most active in a given tumor. The scientists use this signature of gene expression in the cancer cells to predict which chemotherapeutic agent will be most powerful in treating the specific tumor.

In the current study, funded by the National Institutes of Health, the researchers assessed the tests' ability to predict how patients with breast and ovarian cancer and leukemia responded to various anticancer drugs. They found that the tests predicted the clinical response to chemotherapy with 80 percent accuracy.

"Importantly, we believe this research can improve the efficiency of chemotherapy without changing the drugs currently used in standard practice," Nevins said. "Rather, the tests simply provide an approach to better selection, within a repertoire of available drugs."

CDK2/FOXO1 as drug target to Prevent Tumors

Fri, 13 Oct 2006 01:11:00 PST

( from http://www.rxpgnews.com ) Mayo Clinic researchers have found that a protein that initiates a "quality control check" during cell division also directs cell death for those cells damaged during duplication. This knowledge represents a potential "bulls eye" for targeting anti-tumor drugs. The findings appear in the current issue of Science.

The researchers examined a protein called cyclin-dependent kinase 2 (CDK2), which works as a "quality control inspector." As normal cells divide, they pause in the replication process when they find inaccurate genetic code embedded in their DNA. The health and well-being of offspring cells depends on accurate genetic code transfer from one generation of cells to the next. The Mayo researchers showed that when errors in genes are irreparable, CDK2 modifies another cellular protein -- FOXO1 -- to send a signal that results in the death of the cell. This protein-to-protein relationship invites targeted drug intervention to control unregulated growth of cancer cells.

"Quality control within dividing cells is essential because mistakes during duplication of the genetic code can lead to cancer," says Donald Tindall, Ph.D., co-leader of the Mayo Clinic Cancer Center prostate cancer research program. "CDK2 is a key protein component in the cellular mechanism that leads to repair of damaged DNA."

If cells pass this quality control checkpoint, they can resume the process of dividing into two daughter cells. If, however, major irreparable discrepancies occur in the genetic code, cells are shunted toward a molecular sequence that leads to death, or apoptosis. Cells have the genetic knowledge to sacrifice themselves for the greater good of the organism rather than to pass on errant genetic codes that can lead to disease. Genetic errors that sneak past the cell's quality control check-points can make the cell prone to develop into cancer.

The Mayo researchers documented that CDK2 infuses high energy into another cellular protein, FOXO1, switching it on as the initial link in a signal that tells the cell to set itself up for apoptosis. CDK2 adds phosphorylation to a specific serine residue on the chain of amino acids that make up FOXO1. In case of robust errors found in the genetic code, CDK2 signals FOXO1 to explicitly call for the cell to produce a set of proteins leading to apoptosis.

"If the cell has minor alterations in the DNA code that can be repaired, those repairs are made," says first author Haojie Huang, Ph.D. "If the genetic message cannot be repaired, our studies show that CDK2 can initiate the steps necessary for cells to order the production of genes involved with cell death, and the errant cell dies without propagating its damaging genetic message to progeny cells of its own."

"As patients and their physicians seek to control or cure tumors, research is providing new approaches to limiting cancer from growing and spreading," Dr. Tindall said. "With this new understanding of the biology driven by critical dual functions of CDK2, the cancer community can focus on ways to regulate a mechanism that the cell contains to prevent damaged genetic messages from being inherited and spread in proliferating tumor cells."

Telomerase inhibitors may revolutionize cancer therapy

Thu, 21 Sep 2006 20:19:00 PST

( from http://www.rxpgnews.com ) A new target for cancer therapy has been identified by Monash University scientists investigating the cell signalling pathways that turn on a gene involved in cancer development.

A team led by Associate Professor Jun-Ping Liu, from the Department of Immunology, has identified two proteins that are involved in stopping the gene from producing a protein called telomerase that is essential if cancer cells are to proliferate.

Telomerase plays a key role in controlling the life span of cells by modifying structures called telomeres that are found at the end of chromosomes.

Although it is involved in tumour development, telomerase is also found in modest quantities in most cells. It is plentiful in stem cells where it keeps the telomeres long, allowing the cells to keep dividing without limit which is necessary for the repair of damaged and worn out tissues throughout the human body.

However, studies have shown that telomerase also plays a key role in the formation of cancerous tumours. "It's the best indicator of cancer -- 85 per cent better than any other tumour marker," Associate Professor Liu said. "What's more, telomerase is not associated with benign tumours; it's a marker for malignant tumours only.

"If we can control the production of telomerase we can prevent the immortality of cancer cells and therefore cancer formation."

Associate Professor Liu and his colleagues have been investigating breast cancer cells to identify the molecular signalling that is required to turn on, and also inhibit, the gene that produces telomerase. They have found two proteins - Smad3 and c-Myc - that are involved in turning off telomerase production. Their findings are published in the current issue of the Journal of Biological Chemistry.

"It's significant to find inhibitors of telomerase and we have found, for the first time, the pathway that inhibits telomerase in human cells," Associate Professor Liu said.

"This reveals an important mechanism for developing anti-cancer agents that mimic these proteins and thereby inhibit the production of telomerase. "

First ever shots of the cervical cancer vaccine administered in Queensland

Tue, 29 Aug 2006 03:41:00 PST

( from http://www.rxpgnews.com )

The vaccine prevents four of dozens of strains of the human papillomavirus (HPV) which cause genital warts and cervical cancer.

UQ Professor Ian Frazer administered the first shots of the cervical cancer vaccine Gardasil in Queensland this afternoon at the Princess Alexandra Hospital.

Rochedale sisters Emma and Rachel McMillan were the first teenage recipients of the Australian-made vaccine which Professor Frazer and his late research partner Dr Jian Zhou helped create.

The vaccine prevents four of dozens of strains of the human papillomavirus (HPV) which cause genital warts and cervical cancer.

The prescription-only vaccine is distributed in Australia and New Zealand by Melbourne based pharmaceutical manufacturer CSL and distributed worldwide by US drugmaker Merck & Co.

It sells for $465 for a three-dose shot but there are plans to have it considered for subsidy under the Pharmaceutical Benefits Scheme and eventually added to the national vaccination program for girls aged 12.

Professor Frazer, the immunologist named 2006 Australian of the Year for his team's work on the vaccine, is the Director of UQ's Centre for Immunology and Cancer Research.

Queensland Treasurer Anna Bligh announced a new Senior Smart State Fellowship at the vaccine launch in honour of Dr Zhou.

Ms Bligh said the three-year, $450,000 Jian Zhou Fellowship would be offered to a Queenslander to advance research and development in immunology and cancer research.

The State Government will contribute $100,000 a year for three years, matched by a $50,000-a-year commitment from CSL.

Professor Zhou's son Andreas, a 20-year-old industrial design student, said he was proud of his father's legacy.

"We're really happy that the vaccine has come through with 100 percent on the test trials but also really sad because my father can't be here with us today," Mr Zhou said.

"We're happy it's finally out there and people can start getting vaccinated."

Gardasil has been approved for use in girls and women aged nine to 26 in Australia and the US.

Cervical cancer kills about 270,000 women worldwide each year.

HPV causes abnormal cells or tissue growth on the feet, hands, vocal cords, mouth and genitals.

About 60 types of HPV have been identified so far with each strand infecting certain parts of the body.

UQ's main commercialisation company, UniQuest licensed the vaccine technology to CSL in 1994.

The vaccine, predicted to become an international "blockbuster" drug, is expected to become one of the first Australian pharmaceutical successes to result in a fair share of economic flow back into the country.

Gleevec can be toxic to the heart

Mon, 24 Jul 2006 19:27:00 PST

( from http://www.rxpgnews.com ) Gleevec, the wildly successful poster-child of a new generation of cancer drugs aimed at specific targets in the cancer cell, can be dangerous to the heart. Not only that, but other similarly based drugs called tyrosine kinase inhibitors could lead to heart problems as well, say researchers at the Center for Translational Medicine at Jefferson Medical College in Philadelphia.

A team of scientists led by Thomas Force, M.D., James C. Wilson Professor of Medicine at Jefferson Medical College of Thomas Jefferson University, has shown in studies in both mice and in heart cells in culture that Gleevec can cause heart failure. The results of the study, prompted by 10 patients with chronic myelogenous leukemia (CML) who developed severe congestive heart failure while taking Gleevec, appear July 23, 2006, in an advanced online edition of the journal Nature Medicine.

"We found that the molecular target of the drug, the Abelson tyrosine kinase (ABL) protein, serves a maintenance function in cardiac muscle cells and is necessary for their health," Dr. Force explains. "While the cancer is treated effectively, there will be some percentage of patients who could experience significant left ventricular dysfunction and even heart failure from this."

"Gleevec is a wonderful drug and patients with these diseases need to be on it," he says. "We're trying to call attention to the fact that Gleevec and other similar drugs coming along could have significant side effects on the heart and clinicians need to be aware of this. It's a potential problem because the number of targeted agents is growing rapidly."

Gleevec is a new type of cancer drug the first of its kind developed to fight cancer by turning off an enzyme that causes cells to become cancerous and multiply. In CML, an enzyme called ABL goes in overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR become fused and produce a hybrid BCR-ABL enzyme that is always active. The overactive BCR-ABL, in turn, drives the excessive proliferation of white blood cells that is the hallmark of CML.

According to Dr. Force, 10 patients taking Gleevec at the University of Texas' M.D. Anderson Cancer Center in Houston developed fairly severe heart failure, with no prior symptoms. Because physicians there took baseline measures of the patients left ventricular heart function, the team was able to determine that heart failure developed in these patients between two and 14 months after beginning Gleevec.

The research team probed the potential mechanisms behind the drug's possible toxic effects on the heart. Dr. Force explains that at the outset, the scientists couldn't tell if the toxicity was from the drug's effect on the known drug targets, or from an off-target effect or even a non-specific problem. "Sorting that out is important because then we can say, for example, if there are 10 more ABL inhibitors coming on line soon, and if the problem is really with inhibition of ABL, then these may have toxicity problems as well," he says.

The team proved that ABL was the guilty target by using viruses that coded for normal ABL and a Gleevec-resistant mutant. Gleevec inhibited the normal enzyme but not the mutant, and the mutant ABL "rescued" the heart cells from the toxic effects of Gleevec, proving that ABL is the relevant target. As a result, second-generation Gleevec drugs might also have similar toxicities in the heart.

"This finding is a big surprise and there may be a lot more of these," Dr. Force notes. "It's not a class effect like COX-2 inhibitors. The drugs are all tyrosine kinase inhibitors, but each tyrosine kinase is different. It's difficult to predict what tyrosine kinases will have protective roles in the heart and inhibition of them will be toxic."

Newer drugs tend to be 'dirtier' that is, companies are developing drugs that hit multiple cancer cell targets at once to up the chances of effectiveness. Finding the exact target that, when inhibited, can cause problems with the heart, is critical to designing agents to counteract this effect.

In Gleevec, for example, blocking the PDGF receptor is crucial to its effect in thwarting gastrointestinal stromal tumors. Designing a drug to inhibit the PDGF receptor but not ABL, then, could still work against such tumors but not cause heart problems.

"We've learned something about the biology of the heart," Dr. Force says. "ABL is important for cardiomyocyte health. We also can learn something about how to stay away from these targets that are important and optimize the drugs."

In other studies, the researchers attempted to find the biological pathways involved in causing heart cells to die. They found that Gleevec appears to cause endoplasmic reticulum stress, which is initially a protective response by the cell, but if sustained, leads to cell death. They also found that treating mice heart cells with Gleevec led to the cells losing mitochondrial function, leading to cell death.

Jefferson, in collaboration with M.D. Anderson, the Cleveland Clinic and one or more European centers is planning to begin a registry for new tyrosine kinase inhibitors. "As these drugs come out, we can more easily collect data on larger numbers of patients as they take the drugs to get an idea of the incidence of heart problems," Dr. Force explains.

Dr. Force doesn't think it's possible to screen for potential heart problems that could be related to Gleevec. He notes that physicians involved in pre-release clinical trials of tyrosine kinase inhibitors will be aware of the potential problems and evaluate heart function if symptoms or signs possibly due to heart failure appear.

Anti-cancer possibilities seen for certain monoamine oxidase inhibitors

Sat, 24 Jun 2006 16:25:00 PST

( from http://www.rxpgnews.com ) In 2005, professor Ramin Shiekhattar, Ph.D., at The Wistar Institute and his colleagues reported details about an enzyme involved in appropriately repressing sets of neuronal genes in non-neuronal cells.

At the time, the scientists noted that the enzyme appeared to fit into the same extended enzyme family that includes monoamine oxidases, psychoactive enzymes that oxidize dopamine and norepinephrin. Inhibitors of these enzymes have long been used to treat depression, certain other psychiatric and emotional disorders, and Parkinson's disease.

Now, in a study published online today in the June 26 issue of Chemistry & Biology, Shiekhattar and his team show that the enzyme is itself a target for certain monoamine oxidase inhibitors used to treat depression. One member of this family of drugs in particular, called tranylcypromine (brand name Parnate®, manufactured by GlaxoSmithKline), was seen to inhibit the enzyme most strongly. The findings suggest that these anti-depressive drugs may have additional applications in other medically relevant areas.

For example, Shiekhattar notes that the enzyme studied exists in a complex with another type of gene-regulating enzyme that has been implicated in the development of cancer. Inhibitors of that second enzyme are currently in clinical trails as cancer therapies.

"Might particular monoamine oxidase inhibitors, currently used primarily to treat depression, have anti-cancer activity too?" Shiekhattar says. "Our findings indicate this could be the case, and we are currently screening these drugs against many different types of cancer to answer that question."

Because the primary role of the enzyme is to repress sets of related genes, many other areas of potential influence for the monoamine oxidase inhibitors are possible too, according to Shiekhattar. At the very least, he says, the drugs will likely prove to be useful laboratory tools for answering fundamental questions about genetic expression.

The enzyme in question is called BHC110/LSD1, and it was the first human histone demethylase identified. The enzyme's function is to remove methyl groups from small molecules called histones to modify them in ways that trigger gene repression. The second enzyme found in complex with BHC110/LSD1, acts in a similar way. Called a deacetylase, this enzyme removes acetyl groups from histones to repress gene expression.

In the body's scheme for safely storing genes away until needed, DNA is tightly looped around the histones, kept secure by enzymes similar to the ones studied by the Wistar team until made accessible by the activity of other enzymes responsible for gene expression. Eight histones comprise a nucleosome, and long strings of nucleosomes coil in turn into chromatin, the basic material of chromosomes.

AS101 protects the testis from the effects of paclitaxel

Tue, 20 Jun 2006 21:30:00 PST

( from http://www.rxpgnews.com ) It may be possible to protect the testes of cancer patients against the loss of fertility caused by chemotherapy, a scientist told the 22nd annual conference of the European Society of Human Reproduction and Embryology in Prague, Czech Republic on Tuesday 20 June 2006. Mr. Alon Carmely from Bar-Ilan University, Ramat Gan, Israel, said that his work showed for the first time that the injection of a drug that enhances the immune system could protect the testis from the effects of paclitaxel (Taxol), a widely used chemotherapy drug.

"The effects of chemotherapy treatment on fertility are an important issue for long-term survivors of cancer who may not have started or completed a family at the time of diagnosis", said Mr. Carmely. "AS101 is a Tellurium-based non-toxic immunomodulatory compound developed and synthesised by us. Tellurium is a transition element with similar properties to Selenium, which is also known to have many beneficial effects."

Knowing that AS101 had been shown to have chemoprotective effects in both animal and human studies, he and his team decided to investigate whether it could be used to avoid testicular damage in mice treated with Taxol. "Clinical studies had already shown that AS101 could protect against bone marrow damage and hair loss, and also sensitises the tumour to treatment", he said.

The scientists divided the mice into four groups Taxol only, AS101 plus Taxol, AS101 only, and a control group. After 30 days they were euthanized and their testes examined and weighed. The researchers found that a single dose of Taxol had induced significant testicular weight loss compared with the control group. An injection of AS101 a day before that of Taxol prevented the Taxol-induced weight loss.

"Tissue analysis of the testes of Taxol-injected mice showed severe atrophy and empty seminiferous tubules, where the sperm-producing cells are contained", said Mr. Carmely. "In contrast, we saw only minimal testicular damage in the group that had previously been injected with AS101, and we could also find mature sperm. Injection of AS101 alone did not alter testicular weight or tissue analysis results.

"These results hold out much promise for fertility preservation in men undergoing cancer treatments", he said. "We now intend to study the mechanism of protection, which is still unclear. Our work suggests that in addition to the direct damage caused by the treatment, significant testicular damage is caused by the immune reaction to it. We hope to begin clinical studies in cancer patients in the next few months."

Microbeam Radiation Therapy (MRT) Could Improve Cancer Treatment

Sat, 10 Jun 2006 13:38:00 PST

( from http://www.rxpgnews.com ) Researchers at the U.S. Department of Energys Brookhaven National Laboratory and colleagues at Stony Brook University, the IRCCS NEUROMED Medical Center in Italy, and Georgetown University say improvements they have made to an experimental form of radiation therapy that has been under investigation for many years could make the technique more effective and eventually allow its use in hospitals. Results on the improved method, which was tested in rats, will be published online this week by the Proceedings of the National Academy of Sciences.

The technique, microbeam radiation therapy (MRT), previously used a high-intensity synchrotron x-ray source such as a superconducting wiggler at Brookhavens National Synchrotron Light Source (NSLS) to produce parallel arrays of very thin (25 to 90 micrometers) planar x-ray beams (picture the parallel panels of window blinds in the open position) instead of the unsegmented (solid), broad beams used in conventional radiation treatment. Previous studies conducted at Brookhaven and at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France, demonstrated MRTs ability to control malignant tumors in animals with high radiation doses while subjecting adjacent normal tissue to little collateral damage.

But the technique has limitations. For one thing, only certain synchrotrons can generate its very thin beams at adequate intensity, and such facilities are available at only a few research centers around the world.

The new development seeks a way out of this situation, explained Brookhaven scientist Avraham Dilmanian, lead author of the new study. In this paper, the scientists report results that demonstrate the potential efficacy of significantly thicker microbeams, as well as a way to interlace the beams within a well-defined target inside the subject to increase their killing potential there, while retaining the techniques hallmark feature of sparing healthy tissue outside that target.

First, they exposed the spinal cords and brains of healthy rats to thicker (0.27 to 0.68 millimeter) microbeams at high doses of radiation and monitored the animals for signs of tissue damage. After seven months, animals exposed to beams as thick as 0.68 millimeter showed no or little damage to the nervous system.

This demonstrates that the healthy-tissue-sparing nature of the technique stays strong at a beam thickness that is within a range that could be produced by specialized x-ray tubes of extremely high voltage and current, Dilmanian said. Such x-ray sources may become available sometime in the future and may allow the implementation of the method in hospitals.

Next, the scientists demonstrated the ability to interlace two parallel arrays of the thicker microbeams at a 90-degree angle to form a solid beam at a small target volume in the rats brains, and measured the effects of varying doses of radiation on the targeted tissue volume and the surrounding tissue using magnetic resonance imaging (MRI) scans. For interlacing, the gaps between the beams in each array were chosen to be the same as the thickness of each beam, so the beams from one array would fill the gaps in the other to produce the equivalent of an unsegmented beam in the target volume only.

In this way we are effectively delivering an unsegmented broad beam type of dose to just the target region which could be a tumor, or a non-tumerous target we want to ablate while exposing the surrounding tissue to segmented radiation from which it can recover, Dilmanian said.

The MRI scans showed that at a particular dose of radiation, the new configuration could produce major damage to the target volume but virtually no damage beyond the target range. The dose of radiation delivered to the target volume would have been enough to ablate a malignant tumor, Dilmanian said.

These results show that thick microbeams generated by special x-ray tubes in hospitals could eventually be used to destroy selective targets while sparing healthy tissue, Dilmanian said.

Said collaborator Eliot Rosen, a radiation oncologist at Lombardi Comprehensive Cancer Center, Georgetown University, This form of microbeam radiation therapy could improve the treatment of many forms of cancer now treated with radiation, because it can deliver a more lethal dose to the tumor while minimizing damage to surrounding healthy tissue. It may also extend the use of radiation to cases where it is now used only judiciously, such as brain cancer in patients under three years of age, because of the high sensitivity of young brain tissue to radiation.

And according to collaborators David Anschel, a neurologist at Stony Brook University and Brookhaven Lab, and Pantaleo Romanelli, a neurosurgeon from NEUROMED Medical Center, the technique may also have applications in treating a wide range of benign and malignant brain tumors and other functional brain disorders such as epilepsy and Parkinsons disease.

MRT research was initiated by retired Brookhaven scientist Daniel Slatkin, the late Per Spanne, also from Brookhaven, Dilmanian, and others in the early 1990s at Brookhavens NSLS. Since the mid 1990s, the method has been under ongoing investigation also at ESRF.

It is not clear why high dose MRT is effective at killing tumor tissue while sparing healthy tissue. The researchers hypothesize that the normal tissue repairs itself, in part, as a result of the survival between the microbeams of the microvasculatures angiogenic cells. This effect seems to occur more successfully in the normal tissue than in tumors, although other factors also seem to be involved.

Novel EGFR antibody mAb 806 targets tumors but not normal tissues

Tue, 06 Jun 2006 14:41:00 PST

( from http://www.rxpgnews.com ) The Ludwig Institute for Cancer Research (LICR) and Life Science Pharmaceuticals (LSP) today announced the results of the first clinical trial of monoclonal antibody (mAb) 806, which demonstrate that 806 specifically targets epidermal growth factor receptor (EGFR) on a wide range of tumor types but has no uptake by normal tissues. This result is markedly different to other mAbs, which target wild-type (wt) EGFR on normal tissues.

According to Andrew M. Scott, M.D., the Director of LICR's Melbourne Centre for Clinical Sciences and principal investigator on the trial, extensive characterization of both mAb 806 and its epitope have been performed by LICR investigators in Melbourne and New York. "We have shown that the 806 antigen is not exposed on inactive wild-type EGFR, but is exposed on a transitional form of the EGFR. The epitope studies are supported by immunohistochemistry demonstrating that the 806 antibody binds to a broad range of epithelial cancers and to gliomas, but not to normal human tissues. These and other preclinical data suggest that 806 would not have the side-effects observed with other EGFR-targeting mAbs."

The 806 antibody has been licensed exclusively to LSP, which is working closely with LICR investigators to develop its commercial potential. "We think the unique targeting capabilities of 806 represent a new and exciting paradigm for cancer treatment," says James Fiore, President and CEO of LSP. "This mAb has a potent anti-tumor activity, with no targeting of normal tissues, in xenograft models, and now this clinical study has validated its target-specificity and safety in humans."

The clinical trial confirmed the excellent targeting of ch806 to cancers including squamous cell carcinomas of the lung, head and neck and skin, colorectal cancer, mesothelioma and glioma. Importantly, there was no evidence of localization of ch806 to normal tissue. No significant toxicities were observed. The results were published in the Proceedings of the American Society for Clinical Oncology's Annual Meeting being held currently in Atlanta, GA. The mAb 806 is an investigational drug and it is not approved for use in any indication in any country at this time.

Oral chemotherapy option soon for cancer

Tue, 18 Apr 2006 07:20:00 PST

( from http://www.rxpgnews.com ) Swiss pharmaceutical major Roche's study investigating Xeloda (capecitabine) in the first-line treatment of advanced stomach cancer has successfully met its primary endpoint, the company said Monday.

Data from the first-ever phase III clinical study showed that Xeloda, added to another chemotherapy called cisplatin, was at least as effective as the current standard treatment - that uses intravenous 5-fluorouracil plus cisplatin - in terms of time to disease progression, Roche said in a statement.

This international study was a randomised, open-label one of the effect of first-line chemotherapy with Xeloda plus cisplatin versus intravenous 5-fluorouracil plus cisplatin on time to disease progression in patients with advanced or metastatic gastric cancer.

Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. It affects twice as many men as women and occurs more frequently in people aged over 55 years.

Xeloda is licensed in more than 90 countries including the EU, the US, Japan, Australia, Canada and India and has been shown to be an effective, safe, simple and convenient oral chemotherapy.

The oncology market in India is estimated at $30 million. Other cancer drugs from Roche in India include Herceptin and Avastin.

"Full results from the study have been submitted to the American Society of Clinical Oncology (ASCO) for presentation at their annual meeting taking place from June 2-6 in Atlanta, the US," the statement said.

Based on the results of the study, Roche plans to file for an indication in advanced gastric cancer with worldwide regulatory authorities, the company said.

Radiotherapy timings for colon cancer may need adjustments

Sun, 09 Apr 2006 09:58:00 PST

( from http://www.rxpgnews.com ) Scientists have unexpectedly discovered that mice with the gene defect that causes colon cancer in humans can differ from normal mice in how they respond to radiation treatments. The large intestine carrying the gene defect in mice that received staggered doses of radiation was three to four times more resistant to the radiation than in control mice.

The researchers, led by Bruce Boman, M.D., Ph.D., director of the Division of Genetic and Preventive Medicine at Jefferson Medical College Philadelphia and at Jefferson's Kimmel Cancer Center and Dennis Leeper, Ph.D., professor of radiation oncology at Jefferson Medical College, say these results may have implications for treating patients with colon cancer, which is a tumor that frequently has mutations in a gene called APC.

Scientists have known that patients' colon tumors with APC mutations have an increased amount of survivin, a protein that halts apoptosis, the programmed cell death. This increase also appears to be associated with a rise in the number of stem cells found at the bottom of colonic crypts. Researchers wanted to see if there was a difference in stem cell number between normal mice and mice mutant for APC. To do this, they exposed both normal and mutant mice to radiation, testing their ability to repair the resulting DNA damage. They speculated that increased survivin in the mutant mice might enable more stem cells to survive and affect the response to radiation. The researchers asked if mice with an APC mutation are different from normal mice in radiation sensitivity and their ability to repair the damage. Normal cells can repair DNA damage from radiation, Dr. Leeper explains.

They measured the survival of colon crypts in the small and large intestines in normal and mutant mice following radiation exposure, looking at the responses to both single doses of radiation and to staggered or "fractionated" doses of radiation, where the second dose is given five hours after the first dose, again causing the DNA repair to kick in.

"In the normal mouse the radiation-induced damage in the intestine is repaired, just as we expected," Dr. Boman explains. In fact, intestinal cells in both the mutant mouse and normal mouse reacted the same to the single dose of radiation.

But the mutant mice responded differently to the staggered radiation. "When we irradiate five hours later when repair has begun, and damage is being repaired, and then a second dose of radiation is given, the mutant mice are resistant," says Dr. Leeper. More specifically, the Jefferson team found that in the large intestine in the mutant mice, the colon crypt cells were more resistant to radiation by a factor of three to four.

"This is a novel finding." says Dr. Leeper . He notes that the results could have important implications as to how radiation is given to colon cancer patients. "If you are giving radiation once a day, it shouldn't be a problem. But if you are fractionating treatments, given it two or three times a day, this finding could have implications. We would want to make sure that repair processes and signaling receptors come back to baseline before a second dose of chemotherapy is given."

Fibrasorb - New device that could cut chemotherapy deaths

Mon, 03 Apr 2006 07:21:00 PST

( from http://www.rxpgnews.com ) A new method of delivering chemotherapy to cancer patients without incurring side effects such as hair loss and vomiting is being developed.

The method, produced at the University of Bath, England, involves using tiny fibres and beads soaked in the chemotherapy drug which are then implanted into the cancerous area in the patient's body.

These fibres are bio-degradable and compatible with body tissue, which means they would not be rejected by the patient's body. They gradually turn from solid to liquid, releasing a regular flow of the chemotherapy chemical into the cancer site, and a much lower dose to the rest of the body.

This is a more localised way of killing cancer cells than the current method of injecting the chemical into a cancer sufferer's vein so that it is carried around the body.

As well as reducing the side-effects, the new drug delivery vehicle, known as Fibrasorb, could also cut the numbers of patients who die from the effects of chemotherapy because they need such high doses to tackle their cancer.

The method, developed by Dr Semali Perera, of the University's Department of Chemical Engineering, over the past few years, has successfully gone through preliminary laboratory trials. The first clinical trials on volunteer patients with ovarian cancer in Avon, Somerset and Wiltshire could begin in the next few years and, if successful, the technology could be put into general use.

The research team at Bath is collaborating closely with the Avon, Somerset and Wiltshire Cancer Centre and the oncology team at the Royal United Hospital for the design and development of these drug delivery vehicles. This team includes Dr Ed Gilby, one of the most experienced consultant oncologists, surgeons Mr Nicholas Johnson and Mr Kenneth Jaaback, clinical trials experts and specialist nurses such as Tracie Miles.

"Side effects from chemotherapy can be very unpleasant and sometimes fatal," said Dr Perera.

"The new fibres and beads could cut out some side-effects entirely, including nausea and vomiting, and could reduce the number of people who die each year.

"Although the first study will be on patients with ovarian cancer, soon we hope that other cancer sufferers with solid tumours will benefit.

"Give that around one in eight people worldwide die of cancer, this could be a vitally important step in the treatment of this disease.

"We have now assembled an extremely experienced team to develop the Fibrasorb technology."

The Fibrasorb technology is a flexible fully resorbable device that can be formulated as a bead, a fibre or mesh, or as a tube put into the body which leads outside the body and through which drugs can be fed.

For the pre-clinical studies, funded by the Department of Health, Dr Perera will be working closely with Dr Vasanta Subramanian, a lecturer in the University's Department of Biology & Biochemistry. Dr Subramanian is a cell and molecular biologist with extensive research experience in gastrointestinal cancers and stem cells in the gastrointestinal tract.

Dr Perera has also been working with the University's Department of Pharmacy & Pharmacology to make the fibres more sterile so they cannot be attacked by harmful bacteria.

Dr Perera said that other researchers had worked on using tiny beads as a way of delivering drugs locally, but the new system showed greater promise because it could achieve better control when delivering the drug.

Serendipity versus planning - cancer drugs of the future?

Mon, 27 Mar 2006 04:29:00 PST

( from http://www.rxpgnews.com ) New anticancer drugs are usually developed specially for the job, but occasionally they are borrowed from another field of medicine, and applied speculatively in cancer. Tamoxifen was designed as an anti-oestrogen, based on the observation that at least a third of breast cancers depend on female sex hormones such as oestrogen for survival. Tamoxifen has shown to be an exceptionally effective molecule in cancer treatment; It was never planned to be a preventive agent, but so it has proved to be! It is now licensed to be used to prevent breast cancer in certain women at high risk of the disease.

Contrast this with raloxifene, a drug first developed to treat osteoporosis in women. A selective benzothiophene oestrogen receptor modulator (SERM), raloxifene binds to oestrogen receptors as a mixed oestrogen and anti-oestrogen effect. It functions as an oestrogen sometimes (in bones and on lipid metabolism) and as an anti-oestrogen in other target tissues (endometrium and breast). So, it has the potential for producing some of oestrogen's beneficial effects without producing its adverse effects. In a trial of its use in osteoporosis, it appeared to have another completely different effect, namely prevention of new hormone dependant breast cancers.

Results from the MORE (The Multiple Outcomes of Raloxifene Evaluation) study of 7,705 women that were randomised to raloxifene or placebo demonstrated that among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during three years of treatment with raloxifene.

Stronger evidence on the safety and efficacy of raloxifene is awaited from the STAR Trial. This trial includes almost 20,000 postmenopausal women in the US who are at increased risk of breast cancer to determine whether raloxifene is as effective in reducing the chance of developing breast cancer as tamoxifen. Women taking raloxifene demonstrated some side effects and in clinical trials have about three times the chance of developing a deep vein thrombosis or pulmonary embolism as women on a placebo, however there is less risk of cancer of the uterus (a serious side effect of tamoxifen).

An example of a molecule causing much interest in breast cancer treatment is lapatinib, which administered orally. It was designed to hit a subset of the popular Epidermal Growth Factor Receptors (EGFR), which are targeted by other successful agents such as trastuzamab (Herceptin), cetuximab (Erbitux) and gefitinib (Iressa). The first two are monoclonal antibodies, against ErbB2 and ErbB1 respectively, the third is a 'designer' drug. Trials of the combination of antibodies have been promising, so the development of lapatinib to block both receptors via their tyrosine kinase portions is giving rise to optimism. It is a small molecule, like gefitinib, and may have pharmacological advantages over the antibody formulations, such as penetrating the blood-brain barrier.

Early clinical trials with lapatinib suggest that it may hit cancer cells, resistant to other commonly used breast cancer drugs, and to the other EGFR targeting agents, including trastuzamab. Its activity as a single agent is modest, but combination trials already underway are looking promising enough to start randomised comparative large scale investigation. Side effects reported so far suggest a good safety profile, though skin rash, lung and heart effects seen with other members of the drug class will be monitored carefully in the next generation of trials. And, following the example of tamoxifen, it is being tested as a chemo-preventive too.

Scientists one step closer to cancer vaccine

Wed, 22 Mar 2006 01:42:00 PST

( from http://www.rxpgnews.com ) Scientists at Karolinska Institutet in Sweden have helped to identify a molecule that can be used as a vaccination agent against growing cancer tumours. Although the results are so far based on animal experiments, they point to new methods of treating metastases.

The results are presented in the online edition of the prestigious scientific journal Nature Medicine, and represent the collaborative efforts of researchers at KI and Leiden University Medical Centre in Holland.

The study analysed an immunological cell, a T cell, which recognises other cells with defects common to metastasing ones. These defects (which are found in MHC class 1 molecules) allow the tumour cell to evade the "conventional" T cell-mediated immune defence.

The researchers have identified a short peptide molecule that the T cell in the study recognises. Using this peptide, the researchers can vaccinate and protect against the spread of tumours from different tissues, including melanoma, colon cancer, lymphoma, and fibrosarcoma.

"So far we've only conducted research on mice, so it's too early to get out hopes up too much," says research scientist Elisabeth Wolpert at the Microbiology and Tumour Biology Centre. "However, the study does point towards new possible ways of developing a treatment for advanced tumour diseases."

The newly published study is a continuation of an original discovery that first identified the TEIPP-T cell and that was presented in Ms Wolpert's doctoral thesis at Karolinska Institutet in 1998.

The spread of tumours, or metastases, is the most common cause of death from cancer.

Possibility of Separating Anticancer Properties of Vitamin D Revealed

Sun, 19 Mar 2006 20:49:00 PST

( from http://www.rxpgnews.com ) At the right dose, vitamin D is important for bone development and may help protect against the development of several cancers, particularly colorectal cancer. However, large quantities designed to exploit the vitamins anticancer properties can lead to a toxic overdose of calcium in the blood. Now, research done at Georgetown Universitys Lombardi Comprehensive Cancer Center indicates that it may be possible to separate the anticancer properties of vitamin D from its other functions.

Their study, reported in the journal Molecular Cell, found that mutant forms of the protein that binds to vitamin D in the cell do not allow vitamin D to promote bone development and calcium transport but do permit it to regulate an oncogenic protein known as beta catenin. Some modified forms of vitamin D itself, which do not alter bone and calcium, were also found to regulate beta-catenin.

We found that we might be able to separate the two functions at the molecular level, and this raises the possibility that vitamin D can be chemically modified into a drug that will only have anticancer effects, said Professor Stephen Byers, Ph.D. He and Salimuddin Shah, Ph.D., led an international group of investigators in this study.

The human body produces a lot of vitamin D from a brief exposure of the sun. The vitamin is made in the skin when a cholesterol-like molecule interacts with ultraviolet light. It has long been known that a lack of vitamin D can lead to the bone deformities associated with rickets, and the vitamin helps maintain calcium and phosphorous levels in bone and blood. Too much vitamin D, however, can spill calcium into the blood and lead to heart disease and death.

Population studies have also uncovered an interesting fact that the risk of developing colon cancer is lower in people who live in sunny climates. Epidemiology studies have indicated that vitamin D is responsible for the protective effect of sunlight exposure on the incidence of several other cancers besides colon, including breast and prostate.

Byers and the research team suspected that beta catenin may interact with vitamin D in some fashion because of another known fact activation of beta catenin causes most colon cancers.

To help them understand what vitamin D is doing in the cell, the researchers studied findings by other scientists who had looked at families who develop rickets due to an inherited mutation in their vitamin D receptor. Most of these patients had both rickets and alopecia (baldness). However a small number of families had mutations in the receptor which only led to rickets. We know beta catenin is also involved in regulation of hair growth and we wondered if these particular mutations might also allow the receptor to regulate beta catenin, Byers said.

We found a mutation which caused rickets but not alopecia but which still allowed beta catenin to bind to the vitamin D receptor, he said. This suggested to the researchers that it may be possible to separate the anti-cancer role of vitamin D from its effects on bone and calcium.

If a drug mimic of vitamin D can be developed, it could prove useful in preventing some cancers at their earliest stages, but would probably not offer any therapeutic benefit for later stage cancers, Byers said. Thats because we know that by the time colon cancer is well advanced it fails to respond to vitamin D.

Vitamin D can be modified to produce only anti cancer effects

Sat, 18 Mar 2006 02:07:00 PST

Sunitinib Approved for Gastrointestinal Stromal Tumors (GIST) and Kidney Cancer

Sat, 28 Jan 2006 12:29:00 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) today announced approval of Sutent (sunitinib), a new targeted anti-cancer treatment for patients with gastrointestinal stromal tumors (GIST), a rare stomach cancer, and advanced kidney cancer. Today's action marks the first time the agency has approved a new oncology product for two indications simultaneously.

Sutent, which received a priority review and was approved in less than six months, is a tyrosine kinase inhibitor working through multiple targets to deprive the tumor cells of the blood and nutrients needed to grow.

"Today's approval is a major step forward in making breakthrough treatments available for patients with rare and difficult to treat forms of cancer" said Steven Galson, MD, Director of FDA's Center for Drug Evaluation and Research. "New targeted therapies such as Sutent are helping FDA expand options for patients for whom there are limited alternatives."

According to the American Cancer Society, about 32,000 new cases of advanced kidney cancer and 5,000 cases of GIST are diagnosed each year.

Sutent was approved for the treatment of patients with gastrointestinal stromal tumors (GIST) whose disease has progressed or who are unable to tolerate treatment with Gleevec, the current treatment for GIST patients. While studying the treatment in patients, researchers conducted an early (interim) analysis of data that showed Sutent delayed the time it takes for tumors or new lesions to grow in patients with this rare type of stomach cancer. Specifically, the median time-to-tumor progression (TTP) for patients treated with Sutent was 27 weeks compared to 6 weeks for patients who were not treated.

FDA also granted accelerated approval for Sutent in the treatment of patients with advanced renal cell carcinoma (RCC). In contrast to the approval for GIST, which was based on the drug's ability to delay the growth of the tumors, this approval was based on Sutent's ability to reduce the size of the tumors in patients. An overall response rate ranging from 26-37 percent was found in patients with metastatic kidney cancer whose tumors had progressed following cytokine-based therapy.

"Today's approval of this drug for these indications provides compelling evidence that the use of alternative data endpoints allows us to see the benefits of novel therapies earlier in patients," said Richard Pazdur, MD, Director of FDA's Office of Oncology Drug Products.

The FDA has a long-standing commitment of providing patients suffering from serious and life-threatening diseases access to safe and effective treatments, in some cases prior to FDA approval. In the GIST clinical trial, significant clinical benefit was determined through an early interim analysis of data, thereby allowing researchers to convert all patients in the trial to treatment. For the RCC indication, the FDA used its accelerated approval process, a regulatory mechanism that expedites drug approvals for serious and life-threatening diseases.

FDA worked with the product sponsor to offer an expanded access program prior to approval, making the product available to patients not enrolled in a clinical trial. Currently, more than 1700 patients are being treated with Sutent through the expanded access program.

"Expanded access programs have proven to be an effective way to get treatment to patients who need it most, especially in cancer," said Ellen Stovall, President of the National Coalition of Cancer Survivorship. "There needs to be a greater awareness among patients and doctors about both the option to participate in clinical research as well as in these expanded access programs in order to make promising new therapies available to as many patients as possible."

The most commonly reported Sutent-related side effects included diarrhea, skin discoloration, mouth irritation, weakness, and altered taste. Patients treated with Sutent also experienced, fatigue, high blood pressure, bleeding, swelling, and taste disturbance. Hypothyroidism was also observed.

AKT blocks cancer cell motility

Wed, 23 Nov 2005 04:57:00 PST

( from http://www.rxpgnews.com ) In investigating the molecular mechanisms of cancer cell motility â€“ the unique property that enables cancer to spread from its primary origin to other parts of the body â€“ researchers have uncovered a surprising role for the AKT/PKB (protein kinase B) enzyme, providing important new insights into cancer metastasis and suggesting that current efforts to develop cancer therapies by inhibiting AKT may be inadvertently promoting the spread of the disease.

Led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) and described in a study in the Nov. 23 issue of the medical journal Molecular Cell, the research demonstrates for the first time that AKT, which is known to increase cancer cells' survival capability also paradoxically increases their motility and invasion abilities, thereby preventing cancer from spreading.

"The aggressive behavior of malignant cancer cells is determined by a complex array of signaling pathways that regulate key functions including cell proliferation, survival capacity, and the ability to migrate from their original location and invade other regions of the body," explains the study's senior author Alex Toker, Ph.D., a member of the department of pathology at BIDMC and associate professor of medicine at Harvard Medical School.

In the 1990s AKT, a component of the phosphoinositide 3-kinase (PI3K) signaling pathway, was first found to promote cancer cells' survival capacity, and since then the enzyme has also been shown to control cell proliferation.

"In essence, cancer cells have highjacked this enzyme and its regulatory proteins in order to increase their ability to survive," explains Toker. "By blocking the pathway â€“ and thereby causing cell death -- AKT has become a popular target in the development of cancer inhibitor drugs."

Although cell migration is an essential feature of the invasive phenotype of cancer cells, relatively little information has been available on AKT's role in this key function. As a result, the discovery that this kinase actually blocks cancer cell motility and invasion was totally unexpected. "We asked ourselves, 'how is this happening?'"says Toker.

The answer, he explains, may lie in a discovery made in his laboratory in 2002, when a transcription factor known as NFAT was identified in aggressive carcinomas of the breast and colon. (Until that point, NFAT was primarily known for its role in providing the body's immune system with a line of defense against infection.)

"Our new findings suggest that it is an NFAT-dependent mechanism that is allowing AKT to block cancer cell motility and subsequent invasion," explains Toker. "Earlier animal studies have shown that although tumors are more likely to develop in the mammary tissue of mice expressing excessive AKT, these animals actually develop fewer metastatic lesions than do control mice. Taken together with our new findings, these results suggest that by inhibiting AKT, not only do you block cancer survival, you also increase cells' properties of motility and invasiveness."

In other words, he says, while a majority of cancer cells will die, those that are able to escape death will be left with a far stronger ability to metastasize and spread to other parts of the body.

"This paper is important because it shows that a pathway known to be involved in initiating breast cancer, the PI3K/AKT pathway, also plays a paradoxical role in suppressing the ability of the tumor to invade new tissues," says Lewis Cantley, PhD, director of the division of signal transduction at BIDMC and professor of systems biology at HMS, in whose laboratory the PI3K pathway was first discovered. "This new discovery suggests that tumors that result from activation of the PI3K/AKT pathway are unlikely to be metastatic unless another mutation occurs to circumvent the block on invasion. The results also suggest that the status of the NFAT pathway that is implicated in invasion should be evaluated in breast tumors."

The study also points out the extremely complex nature of cancer cell pathways.

"We now know that AKT has very different â€“ even competing â€“ functions in its dual roles as both a survival kinase and a motility kinase," says Toker. "In terms of developing future therapies, this poses a host of new questions and challenges and above all, indicates that much more work is needed to arrive at a comprehensive picture of the role of AKT in cancer before it can be targeted for therapeutic purposes."

Cetuximab to be Considered for the Treatment of Squamous Cell Carcinoma of the Head and Neck

Tue, 01 Nov 2005 02:18:00 PST

( from http://www.rxpgnews.com ) ImClone Systems Incorporated and Bristol-Myers Squibb Company announced today that the U.S. Food and Drug Administration (FDA) has notified ImClone Systems that it has accepted for filing the Company's supplemental Biologics License Application (sBLA) for ERBITUX(R) (Cetuximab), an IgG1 monoclonal antibody, in the treatment of Squamous Cell Carcinoma of the Head and Neck (SCCHN). The application seeks approval for use of ERBITUX in combination with radiation for locally or regionally advanced head and neck cancer, and as monotherapy in patients with recurrent and/or metastatic disease where prior platinum-based chemotherapy has failed or where platinum-based therapy would not be appropriate.

The Companies also announced that the ERBITUX sBLA has been granted priority review. The FDA grants priority review to biologics that potentially offer a significant therapeutic advance over existing therapies for serious or life-threatening diseases. Based on the priority review designation, the FDA has six months from the submission date of August 30, 2005, to take action on the sBLA filing.

About Head and Neck Cancer

According to the American Cancer Society, approximately 40,000 Americans will be diagnosed with head and neck cancer this year, including cancers of the tongue, mouth, pharynx, and larynx. In addition, it is estimated that more than 11,000 will die from the disease in 2005 in the U.S.

About ERBITUX(R) (Cetuximab)

On February 12, 2004, the FDA approved ERBITUX for use in the United States in combination with irinotecan in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. The effectiveness of ERBITUX for the treatment of colorectal cancer is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in metastatic colorectal cancer patients.

ERBITUX binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.

Important Safety Information

Severe infusion reactions, rarely fatal and characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension, have occurred in approximately 3% (20/774) of patients with the administration of ERBITUX. Most reactions (90%) were associated with the first infusion of ERBITUX despite the use of prophylactic antihistamines. Severe infusion reactions require immediate and permanent discontinuation of ERBITUX therapy. Caution must be exercised with every ERBITUX infusion as there were patients who experienced their first severe infusion reaction during later infusions. A 1-hour observation period is recommended following the ERBITUX infusion. Longer observation periods may be required in patients who experience infusion reactions.

Severe cases of interstitial lung disease (ILD), which was fatal in one case, occurred in less than 0.5% of 774 patients receiving ERBITUX.

Dermatologic toxicities, including acneform rash (11% of 774 patients, grade 3/4), skin drying and fissuring, inflammatory or infectious sequelae (e.g., blepharitis, cheilitis, cellulitis, cyst) and paronychial inflammation (0.4% of 774 patients, grade 3) were reported. Sun exposure may exacerbate any skin reactions.

Hypomagnesemia has been reported with ERBITUX when administered as a single agent and in combination with multiple different chemotherapeutic regimens. The incidence of hypomagnesemia (both overall and severe [NCI CTC grades 3 & 4]) was increased in patients receiving ERBITUX alone or in combination with chemotherapy as compared to those receiving best supportive care or chemotherapy alone based on ongoing, controlled clinical trials in 244 patients. Approximately one-half of these patients receiving ERBITUX experienced hypomagnesemia and 10-15% experienced severe hypomagnesemia. Electrolyte repletion was necessary in some patients, and in severe cases, intravenous replacement was required. Patients receiving ERBITUX therapy should be periodically monitored for hypomagnesemia, and accompanying hypocalcemia and hypokalemia during, and up to 8 weeks following the completion of, ERBITUX therapy.

Other serious adverse events associated with ERBITUX in clinical trials (n=774) were fever (5%), sepsis (3%), kidney failure (2%), pulmonary embolus (1%), dehydration (5% in patients receiving ERBITUX plus irinotecan, 2% receiving ERBITUX as a single agent) and diarrhea (6% in patients receiving ERBITUX plus irinotecan, 0.2% with ERBITUX as a single agent).

Additional common adverse events seen in patients receiving ERBITUX plus irinotecan (n=354) or ERBITUX as a single agent (n=420) were acneform rash (88%/90%), asthenia/malaise (73%/48%), diarrhea (72%/25%), nausea (55%/29%), abdominal pain (45%/26%), vomiting (41%/25%), fever (34%/27%), constipation (30%/26%) and headache (14%/26%).

How antigen presenting cells are crucial to graft-versus-leukemia's cancer-killing effect

Mon, 17 Oct 2005 19:30:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Michigan's Comprehensive Cancer Center have discovered the secret weapon behind the most powerful form of cancer immunotherapy known to medicine.

Scientists call it the graft-versus-leukemia effect, and it occurs when new immune cells from donated bone marrow, called the graft, attack malignant cells in the patient and destroy them. This intense immune reaction between donor and host cells, which follows a bone marrow transplant from a healthy donor, has saved the lives of thousands of patients with leukemia, lymphoma and other types of blood and immune system cancers.

In a study to be published Oct. 16 in the advanced online edition of Nature Medicine, U-M scientists describe how antigen presenting cells are crucial to graft-versus-leukemia's cancer-killing effect.

The discovery is significant, because it could help make cellular immunotherapy safer, more effective and an option for more cancer patients especially those for whom a donor is unavailable or those who cannot tolerate the procedure's side-effects.

"We already knew that donor T cells were important for an effective GVL response, but now we know there's another cell the antigen presenting cell or APC which plays a critical role in the process," says James L.M. Ferrara, M.D., who directs the U-M Cancer Center's Blood and Marrow Transplant Program.

Antigen presenting cells are rare immune system cells, which look something like a starfish. Their job is to digest proteins called antigens from foreign cells or pathogens and present them to T cells. This alerts the immune system to prepare to fight the invader. When APCs present cancer cell proteins to T cells, the T cells are primed to attack the cancer.

"We found that without functional APCs to process and present antigens to T cells, there is no graft-versus-leukemia response, and the cancer is likely to return," says Pavan R. Reddy, M.D., an assistant professor of internal medicine in the University of Michigan Medical School, who led the research study.

According to Reddy, the research results suggest that manipulating the number and activity of APCs could improve the GVL response, while reducing the risk of a common post-transplant complication called graft-versus-host disease, or GVHD.

"GVHD occurs when the donor's immune cells attack the patient's skin, liver and gastrointestinal tract," Reddy explains. "It triggers a massive inflammatory reaction that can kill the patient, especially if he or she is older or has other medical problems."

In an effort to eliminate GVHD, other researchers have suggested removing APCs from transplanted donor cells, according to Ferrara. "We know that APCs are involved in graft-versus-host disease, so people say let's take out the APCs and then we will get the anti-cancer effect without the risk of GVHD," he explains. "This paper says, no, you can't do that.

"There's a tight link between the graft-versus-leukemia effect and graft-versus-host disease," Ferrara says. "Few patients get the beneficial effects of GVL without some degree of the toxic side effects of GVHD. But if we can find ways to reduce GVHD's toxic effects, immunotherapy could become a viable option for many more cancer patients."

To study what happens during the graft-versus-leukemia effect, Reddy and his U-M colleagues used high doses of radiation to destroy the blood and immune systems of genetically different laboratory mice. After reconstituting each animal's immune system, using either functional or non-functional APCs, the mice were inoculated with cancer cells and given a bone marrow transplant that could cure the cancer. The scientists then determined which mice died from acute graft-versus-host disease, which mice died from cancer and which mice generated a GVL response to destroy the cancer cells.

"The donor and host mice were paired in ways to make their antigen-presenting cells dysfunctional, either because they were of the same tissue type as the donor, or because they had a mutation that prevented them from displaying tumor antigens to T cells," Reddy explains. "Essentially we created animals where the tumor was the same, the antigens were the same, donor T cells were the same, but the APC was dysfunctional. Without a functioning APC, there was no graft-versus-leukemia effect."

Other researchers have suggested that tumor cells can present antigens to T cells directly to stimulate an immune response against cancer, but results from the U-M study indicate the response is too weak to be effective.

"APCs shred proteins, or antigens, from cancer cells and display those shredded proteins on their surface," Ferrara says. "Cancer cells have the same proteins, but haven't gone through the APC's shredding process. It's as if APCs are master chefs who prepare the antigens in a way to make them especially delicious to T cells. So instead of taking just one bite, they go back for seconds or thirds."

In future research, U-M scientists will explore how to manipulate APC function in ways that will preserve their vital role in stimulating an immune response against cancer, while controlling the intensity of graft-versus-host disease. Reddy and Ferrara have studied drugs called HDAC inhibitors and found that they modulate APC function in mice. They hope to design an initial study of these drugs in post-transplant leukemia patients within a year.

Cranberry Compound Can Prevent Metastasis

Mon, 17 Oct 2005 19:25:00 PST

( from http://www.rxpgnews.com ) Scientists have discovered a new compound in cranberries that works in a completely new way to prevent metastasis, the spread of cancer to other parts of the body.

Catherine Neto from the University of Massachusetts-Dartmouth discovered the compound, which prevents cancer cells from breaking away from the primary site and spreading to other parts of the body, a process called metastasis. It inhibits the molecular scissors on the cell surface that snip away at the anchors holding cancer cells in place.

The cranberry compound inhibits the growth of human lung, colon and leukaemia cells in culture, but does not affect healthy cells. These findings are published in the Journal of the Science of Food and Agriculture.

Navindra Seeram, UCLA Centre for Human Nutrition, says that the effect of this compound is new finding, and that the newly identified compound could form the basis of a new cancer drug. Related compounds in red wine are more active in alcohol, and Seeram thinks the same could be true for this compound.

Response to Cancer Vaccine Enhanced by Chemotherapy

Wed, 05 Oct 2005 04:17:00 PST

( from http://www.rxpgnews.com ) A study of a cancer vaccine in mice has found that the vaccine induces a tumor-specific immune response that is enhanced when used with chemotherapy regimens that include 5-fluorouracil (5-FU).

Chemotherapy drugs such as 5-FU inhibit the activity of the enzyme thymidylate synthase (TS), which is necessary for DNA synthesis and cell replication and is often overexpressed in cancer cells. Tumor cells usually respond to the drug exposure by temporarily enhancing the production of this enzyme. Tumor cells can become resistant to 5-FU if they are able to overproduce TS or have mutated enzyme. To determine whether this treatment limitation could be overcome using a peptide vaccine, Pierpaolo Correale, M.D., Ph.D., and Maria Cusi, Ph.D., of Siena University in Italy, and colleagues evaluated mice vaccinated with a peptide (TS/PP) designed to target the enzyme TS.

They report that, in mice vaccinated with TS/PP and subsequently inoculated with TS-expressing lymphoma cells, tumor formation was either delayed or prevented, especially when the mice were also treated with 5-FU. The authors conclude that TS/PP could induce a tumor-specific response in mice and suggest that such a vaccine could have clinical application in humans.

In an editorial, Carmen J. Allegra, M.D., of the Network for Medical Communication Research in North Potomac, Md., and Richard W. Childs, M.D., of the National Heart, Lung, and Blood Institute, note that this vaccine approach, if translatable into the management of human cancer, would be remarkable but caution that it requires additional preclinical study of potential barriers to clinical use in patients.

Marine toxins can knock out the cancer cells

Wed, 28 Sep 2005 07:59:00 PST

( from http://www.rxpgnews.com ) The research team has defined the structure of the toxins and provided a basic understanding that can be used to synthesize pharmaceuticals, according to a study published this week in the Proceedings of the National Academy of Sciences (PNAS).

"We've determined how this class of toxins interacts with actin," an important protein responsible for cellular structure and movement, says Ivan Rayment, a professor of biochemistry in the College of Agricultural and Life Sciences who worked with John Allingham, a postdoctoral fellow, on the study. "We're adding to fundamental understanding which will be taken up by others to simplify chemical synthesis of what could potentially be powerful cancer treatments."

The toxins, which are produced naturally by organisms that exist symbiotically on deep-sea sponges, work by disrupting the activity of actin, an abundant protein that gives structure to eukaryotic cells.

"Actin forms long chains, or filaments, that are essential for cellular locomotion, division and growth," explains Allingham. "Because cancer cell masses grow faster than other cells in the body, actin provides an excellent target for drugs that could inhibit such rapid growth."

Adds Allingham: "These marine toxins can knock out the lynchpins in these long chains or cap their ends and kill cancer cells. Moreover, initial work shows that even a low dose of these toxins can bring a significant response."

Prior to the study published in PNAS, it was known that the marine toxins affect several forms of cancer - but not how they worked, says Rayment. The recent findings will enable the toxins to be synthesized in a lab instead of harvested from the depths of the ocean floor, meaning that the drugs can be engineered to be as effective as possible.

"In order to chemically synthesize a better drug, it is a good idea to know how the natural compound works," he says. "Scientists who study natural products take their cues from what nature has already done. We're adding deep biochemical meaning to this area."

He adds that synthetic chemists hope that actin-based drugs might one day rival the success of Taxol, a powerful drug derived from a natural product that keeps breast-cancer cells from dividing.

"Actin-based drugs have not yet been used as successful drugs as have those that target microtubules, like Taxol, in part because we haven't understood how to target actin," Rayment explains.

"Hitchhiking" Viruses as Cancer Drug Delivery System

Mon, 19 Sep 2005 12:40:00 PST

( from http://www.rxpgnews.com ) A Mayo Clinic research team has devised a new virus-based gene therapy delivery system to help fight cancer. Researchers say their findings will help overcome hurdles that have hindered gene therapy cancer treatments.

The Mayo research team, which includes a collaborator from the United Kingdom, describes its new approach in the current edition of Nature Medicine. The approach relies on "therapeutic hitchhikers" -- particles derived from retroviruses (RNA-containing viruses that incorporate into the genomes of infected cells and then produce a therapeutic gene). The viral particles attach to a specific kind of T cell in the immune system and "hitchhike" to the tumor because T cells home in on tumors naturally; T cells are the immune system's major line of defense against tumors. By hitching a ride on the T cells, the therapeutic particles can hit their tumor target while avoiding detection (and destruction) by the immune system. When the Mayo team experimented with the hitchhiking approach in mice using human and mouse cancer cells, they observed significant cure rates of metastatic -- or spreading -- tumors.

"Any clinical situation in which cells home to disease sites -- such as inflammation or autoimmune disease -- might benefit from this approach," explains Richard Vile, Ph.D., Mayo Clinic molecular immunologist and lead researcher of the investigation. "Our work is an important contribution to the maturation of the field of gene therapy because ultimately treating cancers by gene therapy depends on scientists' ability to specifically target tumor cells in the patient -- and this specific-delivery feature has eluded researchers for a variety of reasons. But by devising a way for viruses to hitch rides on antigen-specific T cells, we've been able to get over multiple obstacles to gene therapy."

Dr. Vile emphasizes that the work is still experimental and not yet ready for use in human patients. But if larger studies validate these findings, the therapeutic hitchhiker approach may be employed in clinical trials of new treatments.

The Mayo investigators have invented a simpler method for using modified viruses to transport therapeutic genes to tumors. They are the first to exploit traits of retroviruses during the infection process of a cell in which attachment to the cell can occur in a nonspecific way. This opens up new opportunities for using viruses therapeutically because this method of attachment allows researchers not only to target particular cells, but also to more easily gain entry into the cells -- which they must do to deliver therapeutic genes to destroy tumors. The T cells also help kill tumors.

Using mice, the Mayo Clinic team showed that retrovirus particles could successfully attach to the surface of primary T cells and then safely hitchhike -- be carried through the bodies of mice that had fully functioning immune systems and evade detection by the immune system -- to reach tumors, the sites of T cell accumulation. They further showed that once it reached the tumor, the viral transporter successfully transferred a gene to both mouse and human tumor cells that then infected the cells. This proved that the concept works.

Pegfilgrastim Significantly Reduces the Incidence of Febrile Neutropenia

Fri, 16 Sep 2005 10:13:00 PST

( from http://www.rxpgnews.com ) Amgen (Nasdaq: AMGN), the world's largest biotechnology company, today announced that the U.S. Food and Drug Administration (FDA) approved an update to the Neulasta(R) (pegfilgrastim) prescribing information to include data from a landmark Phase 3 study demonstrating the white blood cell booster helps protect patients with most types of cancer undergoing moderately myelosuppressive chemotherapy from infection, as manifested by febrile neutropenia (low white blood cell count with fever), one of the most serious side effects of chemotherapy.

Previously, first and subsequent cycle administration of Neulasta to stimulate production of infection-fighting white blood cells was indicated for patients receiving myelosuppressive chemotherapy associated with a more than 30 to 40 percent risk of febrile neutropenia.

Administration of Neulasta beginning in the first cycle of chemotherapy is now approved for patients receiving myelosuppressive chemotherapy associated with at least a 17 percent risk of febrile neutropenia. Myelosuppressive chemotherapy is toxic to the bone marrow where white blood cells, red blood cells and platelets are produced.

"The Phase 3 study demonstrated that administering Neulasta beginning in the first chemotherapy cycle reduced the incidence of febrile neutropenia by 94 percent," said Willard Dere, M.D., chief medical officer and senior vice president of Global Development at Amgen. "With this approval and Neulasta's once-per-cycle dosing, physicians can help protect appropriate patients proactively before their white blood cell counts become dangerously low."

The expanded label was based on a randomized, placebo-controlled study of 928 metastatic or non-metastatic breast cancer patients that was published in the Journal of Clinical Oncology earlier this year. First and subsequent-cycle administration of Neulasta resulted in a 94 percent reduction in the incidence of febrile neutropenia (1 percent versus 17 percent with placebo), a 93 percent reduction in the incidence of hospitalization (1 percent versus 14 percent with placebo) and an 80 percent reduction in the incidence of intravenous anti-infective use (2 percent versus 10 percent with placebo), compared to placebo, in patients receiving moderately myelosuppressive chemotherapy.

"Approximately two-thirds of neutropenic complications happen in the first cycle of chemotherapy," said study lead investigator Charles Vogel, M.D., Cancer Research Network, Plantation, Fla. "This study demonstrates that administering Neulasta beginning in the first cycle of chemotherapy reduces the chance of patients developing an infection."

About Neutropenia

Neutropenia is an abnormally low level of neutrophils, important infection-fighting white blood cells, in the blood stream. Neutropenia can put some patients at risk for severe infections and interruptions in cancer treatment. In fact, complications associated with a low white blood cell count are a common cause of dose reductions or delays in chemotherapy.

Febrile (or feverish) neutropenia is the most common presentation of infection in patients receiving chemotherapy. Infection in this setting can be serious and even life threatening because chemotherapy can compromise the patient's ability to fight infection.

Although white blood cell boosters have been available for more than a decade, only 17 percent of patients receiving myelosuppressive chemotherapy currently receive proactive first-cycle protection from neutropenic complications, which include infection, hospitalization and anti-infective use. Approximately half of the 1.3 million patients receiving chemotherapy are at risk for developing neutropenia.

About Neulasta

Neulasta was approved by the U.S. Food and Drug Administration (FDA) in 2002 for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Similar indications for Neulasta were approved in Europe and Australia the same year.

Rare cases of splenic rupture and sickle cell crises have been reported in postmarketing experience. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment.

In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta treated patients as compared to placebo-treated patients (31 percent vs. 26 percent). The most common adverse events reported in either active or placebo controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain. While not reported in patients receiving Neulasta, rare events of adult respiratory distress syndrome have been reported in patients receiving the parent compound, Filgrastim.

Ligand Treatment of Treg Cells Enhanced Anti-Tumor Immunity

Wed, 14 Sep 2005 02:08:00 PST

( from http://www.rxpgnews.com ) A special stretch of genetic material may turn off the immune suppression that stymies attempts to fight cancer with a vaccine, said researchers at Baylor College of Medicine (BCM) at Houston.

In a report in today's issue of the journal Science, Dr. Rong-Fu Wang, a professor in the BCM Center for Cell and Gene Therapy and Department of Immunology, and his colleagues describe a new strategy to turn off the function of a special group of T cells to suppress immune response to tumors and even infectious diseases.

"Since 1995, many groups have tried to develop a vaccine for the treatment of cancer," said Wang, also a member of the faculty of the BCM Graduate School of Biomedical Sciences. "The only problem is that after 10 years of clinical trials, the data suggest that you can induce (cancer) antigen-specific immune responses, but such responses are too weak and transient to eradicate tumor cells."

The answer lies in a group of cells called CD4+ regulatory T cells (Treg for short). These cells have the ability to suppress the body's natural immune response. If they are depleted, autoimmune diseases will result because the immune system is unchecked and goes on to attack the body's own tissues.

His group previously reported the existence of tumor-specific Treg cells at tumor sites. "Thus, the tumor cells use these Treg cells to protect themselves," said Wang. "In fact, tumor cells can actively recruit and activate them to turn on their immune suppressive function."

One way to stop this action is to simply wipe out the cells with chemoagents or a specific antibody.

"But you may also deplete the good cells needed for fighting cancer," said Wang.

He and his group identified particular ligands (a special stretch of guanosine-containing DNA material) that can bind specifically to a particular receptor called human Toll-like receptor 8 and then turn off the suppressive function of Treg cells.

Treatment of Treg cells with these ligands converts suppressive Treg cells into non-suppressive T cells.

"In fact, in some cases, this treatment actually enhanced anti-tumor immunity," he said.

He hopes that clinical trials with these special ligands in patients with cancer can get underway quickly.

"It could have a huge impact on cancer therapy or treatment of infectious disease," said Wang. "It could boost response to cancer vaccine as well."

Metallic Iron based Magnetic Nanoparticles for Potential New Cancer Treatment

Thu, 08 Sep 2005 01:23:00 PST

( from http://www.rxpgnews.com ) Virginia Commonwealth University researchers have created highly magnetized nanoparticles based on metallic iron that could one day be used in a non-invasive therapy for cancer in which treatment would begin at the time of detection.

We envision a potential for these materials to combine both detection and treatment into a single process, said Everett E. Carpenter, Ph.D., an assistant professor of chemistry at VCU.

Eventually, our goal is to use the scientific understanding of the growth mechanisms of these nanoparticles to develop materials for biomedical applications, said Carpenter. By engineering the magnetic properties of enhanced ferrites it is possible to develop materials for the treatment of various cancers, such as breast cancer.

Carpenter and his team are working to determine how to best construct the core-shell structure and learn which shell materials are most ideal for biomedical applications such as magnetodynamic therapy (MDT), or as MRI contrast enhancement agents.

According to Carpenter, in the future it may be possible for a patient to be screened for breast cancer using MRI techniques with engineered enhanced ferrites as the MRI contrast agent. He said if a tumor is detected, the doctor could then increase the power to the MRI coils and localized heating would destroy the tumor region without damage to the surrounding healthy cells.

Another promising biomedical application is MDT, which employs magnetic nanoparticles that are coupled to the radio frequency of the MRI. This coupling converts the radio frequency into heat energy that kills the cancer cells. European researchers studying MDT have shown that nanoparticles are able to target tumor cells. Carpenter said that because the nanoparticles target tumor cells and are substantially smaller than human cells, only the very few tumor cells next to the nanoparticles are killed, which greatly minimizes damage to healthy cells.

Our goal is to tailor the properties of the nanoparticles to make the use of MDT more universal, said Carpenter. The only thing slowing down the development of enhanced ferrites for 100 megahertz applications is a lack of understanding of the growth mechanisms and synthesis-property relationships of these nanoparticles.

By studying the mechanism for the growth of the enhanced ferrites, it will be possible to create shells that help protect the metallic core from oxidation in biologically capable media, he said.

Enhanced ferrites are a class of ferrites that are specially engineered to have enhanced magnetic or electrical properties and are created through the use of core-shell morphology. He said that in this approach the core can be a highly magnetic material like iron or iron alloys, while the shell can be a mixed metal ferrite with tailored resistivity.

Ferrites (iron oxides) are used in many applications that require both a high magnetization and high electrical resistance; properties which are typically mutually exclusive, said Carpenter. These two properties are tied not only to the structure of the material but also to the way in which the material is synthesized and processed.

Today, polymer encapsulated iron oxide particles are used in biomedical applications. However, Carpenter said that the high magnetization of the enhanced ferrite nanoparticles may potentially improve the absorption of the radio frequency, thereby providing better detection of tumor regions and the use of less MRI contrast re-agent.

In 2002, Carpenter invented a new material based on metallic iron. He said the magnetic power of the iron nanoparticles he created is 10 times greater than that of the currently available iron oxide nanoparticles, which translates to a substantial reduction in the amount of iron needed for imaging or therapy.

Potential Cancer Treatment by Magnetic Nanoparticles

Tue, 30 Aug 2005 20:05:00 PST

( from http://www.rxpgnews.com ) Virginia Commonwealth University researchers have created highly magnetized nanoparticles based on metallic iron that could one day be used in a non-invasive therapy for cancer in which treatment would begin at the time of detection.

We envision a potential for these materials to combine both detection and treatment into a single process, said Everett E. Carpenter, Ph.D., an assistant professor of chemistry at VCU.

Carpenter is discussing his ongoing work of the synthesis and characterization of these functional magnetic nanoparticles for use in biomedical applications at the 2005 American Chemical Society National Meeting & Exposition in Washington, D.C., which began Aug. 28 and continues through Sept. 1.

More than 12,000 researchers from across the country are presenting new multidisciplinary research and highlighting important advances in biotechnology, nanoscience, nanotechnology, and defense and homeland security.

Eventually, our goal is to use the scientific understanding of the growth mechanisms of these nanoparticles to develop materials for biomedical applications, said Carpenter. By engineering the magnetic properties of enhanced ferrites it is possible to develop materials for the treatment of various cancers, such as breast cancer.

Carpenter and his team are working to determine how to best construct the core-shell structure and learn which shell materials are most ideal for biomedical applications such as magnetodynamic therapy (MDT), or as MRI contrast enhancement agents.

According to Carpenter, in the future it may be possible for a patient to be screened for breast cancer using MRI techniques with engineered enhanced ferrites as the MRI contrast agent. He said if a tumor is detected, the doctor could then increase the power to the MRI coils and localized heating would destroy the tumor region without damage to the surrounding healthy cells.

Another promising biomedical application is MDT, which employs magnetic nanoparticles that are coupled to the radio frequency of the MRI. This coupling converts the radio frequency into heat energy that kills the cancer cells. European researchers studying MDT have shown that nanoparticles are able to target tumor cells. Carpenter said that because the nanoparticles target tumor cells and are substantially smaller than human cells, only the very few tumor cells next to the nanoparticles are killed, which greatly minimizes damage to healthy cells.

Our goal is to tailor the properties of the nanoparticles to make the use of MDT more universal, said Carpenter. The only thing slowing down the development of enhanced ferrites for 100 megahertz applications is a lack of understanding of the growth mechanisms and synthesis-property relationships of these nanoparticles.

By studying the mechanism for the growth of the enhanced ferrites, it will be possible to create shells that help protect the metallic core from oxidation in biologically capable media, he said.

Enhanced ferrites are a class of ferrites that are specially engineered to have enhanced magnetic or electrical properties and are created through the use of core-shell morphology. He said that in this approach the core can be a highly magnetic material like iron or iron alloys, while the shell can be a mixed metal ferrite with tailored resistivity.

Ferrites (iron oxides) are used in many applications that require both a high magnetization and high electrical resistance; properties which are typically mutually exclusive, said Carpenter. These two properties are tied not only to the structure of the material but also to the way in which the material is synthesized and processed.

Today, polymer encapsulated iron oxide particles are used in biomedical applications. However, Carpenter said that the high magnetization of the enhanced ferrite nanoparticles may potentially improve the absorption of the radio frequency, thereby providing better detection of tumor regions and the use of less MRI contrast re-agent.

In 2002, Carpenter invented a new material based on metallic iron. He said the magnetic power of the iron nanoparticles he created is 10 times greater than that of the currently available iron oxide nanoparticles, which translates to a substantial reduction in the amount of iron needed for imaging or therapy.

Celecoxib able to control chemotherapy resistant tumor cells

Tue, 30 Aug 2005 19:23:00 PST

( from http://www.rxpgnews.com ) A close structural relative of the celebrated COX-2 inhibitor celecoxib (brand name: Celebrex) is a potent tumor fighter, able to wipe out tumor cells that are resistant to conventional chemotherapies, according to an interdisciplinary team of researchers from the University of Southern California.

Led by Axel H. Schnthal, associate professor of molecular microbiology and immunology at the Keck School of Medicine of USC, the researchers have been studying the effects of an analog of celecoxib that does not have its cousin's celebrated ability to block the activity of cyclooxygenase-2 (COX-2), an enzyme integral to the inflammatory process. Nonetheless, the scientists showed that the analog manages to halt tumor growth even in drug-resistant lines of multiple myeloma cells. (Multiple myeloma is an incurable cancer of the plasma cell; plasma cells are components of the blood, and play a key role in the body's immune response.)

The work was published in the most recent online edition of the journal Blood, and will be appearing in an upcoming print edition of the journal.

Most of the attention celecoxib has received in recent years has been as a result of its anti-inflammatory effects and, most recently, the withdrawal of the two other main COX-2 inhibitors on the market-Vioxx and Bextra-after data unearthed linking them to an increased risk of stroke in some patients. (Celebrex remains on the market, but now carries a "black box" warning about the potential for cardiovascular side effects.)

But the truth is, celecoxib is more than just an anti-inflammatory agent. Over the past couple of years, researchers have begun to recognize that cyclooxygenase-2 can sometimes play a role in cancer; for instance, they've shown that the enzyme is overexpressed by multiple myeloma cells, and that this is a predictor of a poor outcome for the patient. Thus, it seemed clear that a cylooxygenase inhibitor might be able to turn things around.

It did. In several laboratory studies, the COX-2 inhibitor celecoxib showed an ability to target several of the growth pathways; further studies, including some performed by Schnthal and colleagues, showed that celecoxib's anticancer activity appeared to be independent from its COX-2 inhibition. Schnthal's team then went on to show that the analog in question-2,5-dimethyl-celecoxib or DMC-retains the ability to stop cancer growth despite the fact that it doesn't inhibit the activity of COX-2.

"Amazingly," the researchers noted in the Blood paper, "these growth-inhibitory effects take place even in cells that otherwise are highly resistant to the inhibitory effects of various anti-cancer drugs that are commonly used in the clinic for the treatment of cancer patients."

The fact that DMC is as potent-or, says Schnthal, even more potent, even at lower doses-than celecoxib despite having no ability to inhibit COX-2 is important, the researchers say, especially in light of the recently revealed side effects of COX-2 inhibitory drugs. "Bearing in mind that substantially increased daily dosages of these drugs are considered-and probably necessary-for cancer prevention or cancer therapy, the increased risk of cardiovascular failure is of considerable concern," they wrote in the Blood paper. But because the unwanted cardiovascular side effects of celecoxib are connected to its ability to inhibit COX-2, Schnthal speculates that DMC, which lacks that ability, might not cause similar problems.

Schnthal notes that his research points to celecoxib in particular as being unique in its ability to slow or stop tumor growth. All the COX-2 inhibitors are able to block the activity of cyclooxygenase-2, he says, but only celecoxib and its analogs seem able to arrest growth and induce cellular suicide (apoptosis), even in cells that don't produce COX-2.

What does all this mean for the treatment of multiple myeloma? It will be important to extend these current results and determine whether these drugs achieve similar anti-tumor effects in myeloma patients, Schnthal says. "Curing laboratory mice of multiple myeloma isn't good enough," he adds. "But proof of principle has been established with this work, so our next goal will be to evaluate DMC in myeloma patients, perhaps in combination with other drugs.

Inhibiting EAT-2 with medications could boost NK cell activity

Mon, 29 Aug 2005 22:57:00 PST

( from http://www.rxpgnews.com ) Dr. André Veillette, a researcher at the Institut de recherches cliniques de Montréal (IRCM), and his team will publish in the upcoming issue of the prestigious journal Nature Immunology of Nature Publishing Group, a discovery that could significantly advance the treatment of cancers and infectious diseases. Current treatments frequently achieve only limited results with these types of diseases, which affect hundreds of thousands of Canadians.

Dr. Veillette's team identified one of the basic mechanisms controlling NK ("natural killer") cell activity. Produced by the immune system, NK cells are responsible for recognizing and killing cancer cells and cells infected by viruses such as the viruses causing hepatitis and herpes. NK cell deficiency is associated with a higher frequency of cancers and serious infections. Dr. Veillette's breakthrough demonstrates that a molecule known as EAT-2, present in NK cells, suppresses its killer function. Inhibiting EAT-2 with medications could boost NK cell activity, helping to combat cancers and infections.

This publication constitutes a significant milestone for Dr. Veillette, an internationally renowned expert in the identification of the molecular mechanisms controlling the immune system. The article, which is slated for publication online on August 28 in Nature Immunology, gives genetic evidence for the inhibiting role of EAT-2 in NK cells. It is the product of over five years of intensive research by Dr. Veillette's team.

More specifically, by studying mice in which the EAT-2 protein is eliminated through genetic manipulations, Dr. Veillette's team has established that suppressing EAT-2 results in the production of NK cells that are much more effective at killing cancer cells. Inhibiting the function of EAT-2 with medications could therefore stimulate the killer function of NK cells, and increase their capacity to destroy cancer and virus-infected cells. These medications could be used in combination with chemotherapy and radiotherapy to improve the effectiveness of anti-cancer treatments. Teams around the world have been trying without success for many years to develop methods to increase NK cell activity. In this light, the discovery of Dr. Veillette's team opens new avenues for the treatment of cancers and communicable diseases.

Cancer defense by manipulating energy regulation of cells

Sat, 20 Aug 2005 16:35:00 PST

( from http://www.rxpgnews.com ) In an ongoing effort to fight disease by manipulating energy regulation of cells, a collaborative study led by Dartmouth Medical School (DMS) has demonstrated that cells lacking a tumor-suppressing kinase called LKB1 can still maintain healthy energy levels when they become stressed. This energy regulation is essential for keeping cells from dying off too quickly. The study's results could signal new advances for combating cancerous tumor growth, but also type 2 diabetes and obesity.

The study, published in the August 12 issue of the Journal of Biological Chemistry (JBC), was headed by Dr. Lee Witters, Eugene W. Leonard 1921 Professor of Medicine and Biochemistry at DMS and of Biological Sciences at Dartmouth College, who has researched kinases for over 25 years. Kinases encompass a large family of enzyme proteins that play key roles in the workings of most animal cells. He has focused much of his research on the AMP-activated kinase (AMPK) which responsible for managing energy within cellular pathways.

"A cell's energy level is critical to its survival," explains Witters, who likens a low-energy cell to a car with no gas in its tank. "In a previous study, we found that the cellular "gas gauge," AMPK, can turn around and alter any deficits in the cell if it is turned on by the kinase LKB1. In this JBC study, we wanted to see if AMPK could also be turned on by something besides LKB1."

"We decided to work with cervical and lung cancer cells because LKB1 is absent from the cellular pathway," said Rebecca Hurley, lead author of the study and a graduate student in the Molecular and Cellular Biology Program at Dartmouth. Working closely with scientists at St. Vincent's Institute in Australia and Duke University, the DMS team concluded that two kinases in these cancer cells, CaMKKα and CaMKKβ, are able to regulate AMPK independent of LBK1.

"With the addition of these two kinases, we think we have all nearly the players responsible for energy regulation within the cell, which should offer new opportunities in cancer treatment," said Hurley. "If we can stifle a cancer cell's ability to adapt to an energy deficit, it might lose its growth advantage." "You need to know how all these proteins interact before you can make truly significant advances," echoes Witters "It's like poker; not only do you need to know what each card signifies individually, but you must have an understanding of how they play off each other in order to win."

In addition to cancer-fighting potential of AMPK regulation, the enzyme also responds to changes in insulin or glucose and mediates impaired energy metabolism, a hallmark of type 2 diabetes. "This indicates that AMPK is a very tempting target for the treatment of some forms of diabetes and even obesity," said Witters.

Irradiation impairs reading development of young children

Sat, 20 Aug 2005 16:30:00 PST

( from http://www.rxpgnews.com ) Irradiation therapy for the brain cancer medulloblastoma is more likely to impair IQ and reading skills of younger children than older children even if the dose of radiation is reduced, according to the results of the largest study of its kind, conducted by investigators at St. Jude Children's Research Hospital, Texas Children's Cancer Center (Houston) and Royal Children's Hospital (Melbourne, Australia).

The researchers found that the greatest rates of decline in IQ and reading skills occurred in patients who were younger than 7 years old at diagnosis. Patients who were at either high or average risk of treatment failure suffered significant loss of reading skills over time following treatment.

The study used "risk-adapted" radiation therapy in which the dose of radiation was adjusted according to whether the patient's cancer had already spread and how much tumor was left following initial surgery to remove the cancer. Patients in the study were classified as high risk (HR, 37 patients) or average risk (AR, 74 patients) depending on whether they had those risk factors. HR patients were considered more likely to experience treatment failure and therefore received higher doses of radiation.

The loss of reading and spelling skills among both AR and HR children apparently is caused by impairments of the fundamental cognitive processes that are critical to the early development of these skills in a child, according to Amar Gajjar, M.D., a member of the Hematology-Oncology department and director of Neuro-Oncology at St. Jude. Gajjar is the senior author of a report on this study that appears in the August 20 issue of Journal of Clinical Oncology.

In addition to confirming that younger age increases the risk of neurocognitive deficits, the current study also allowed the researchers to develop a way to predict the number of IQ points that would be lost by both HR and AR patients depending on whether they were older (at least 7 years of age) or younger (less than 7 years) at time of diagnosis and treatment.

The investigators are now using results of this study to identify and help children in need of special training to enhance their cognitive functioning following treatment for medulloblastoma.

The study, which included 111 children (age 3-20 at time of diagnosis), was unprecedented because it followed a larger number of patients than any previous such investigation, Gajjar said. In addition, the investigators conducted neurocognitive testing of children for up to six years after diagnosis--that is, both before and after treatment, he added. Moreover, no other such previous prospective study (a study following patients over the course of time) has compared the outcome of children receiving risk-adapted radiation therapy doses.

Risk-adapted treatment included surgery to remove as much of the tumor as possible, followed within 28 days by initial post-operative craniospinal irradiation therapy (CSI) plus a radiation therapy "boost" to the primary (original) tumor site delivered by 3-D conformal radiation therapy (CRT). Six weeks after completion of radiation therapy, children underwent four rounds of chemotherapy with cyclophosphamide, cisplatin and vincristine. The investigators observed the patients every three months for two years and every six months thereafter for a total of five years.

CRT combines CAT scans and MRI to create pictures of the cancer that a computer then turns into three-dimensional images of the tumor. These images are combined with computer-controlled radiation beams and meticulous positioning of the treatment table on which the patient lies. Radiation hits the tumor at precisely calculated angles and depths matching the 3-D image of the tumor, obliterating the cancer and sparing healthy tissue.

All children underwent neurocognitive testing after surgery and at approximately one, two and five years after diagnosis. The IQ of the 104 patients who were at least 3 years old was evaluated using the age-appropriate Wechsler Intelligence Scale; and academic achievement was measured in patients at least 5 years of age using a variety of tests that measured reading, math and spelling skills.

"This study significantly adds to our understanding of the long-term neurocognitive development of these children. It also helps us develop and test intervention programs that aim at reducing the deficits these children experience," said Shawna Palmer, Ph.D., one of two lead neuropsychologists on the study.

Some Cancer Patients Treated With Cetuximab May Require Magnesium Supplementation

Fri, 19 Aug 2005 04:59:00 PST

( from http://www.rxpgnews.com ) Some cancer patients being treated with cetuximab (Erbitux) may develop abnormally low blood levels of magnesium (hypomagnesemia) and require supplementation, according to a new study.

Cetuximab--a monoclonal antibody against the epidermal growth factor receptor (EGFR)--is used to treat patients with metastatic colorectal cancer and is being evaluated for the treatment of several other solid tumors. After treating a 34-year-old male colorectal cancer patient who developed profound fatigue and hypomagnesemia while on cetuximab therapy, Deborah Schrag, M.D., of Memorial Sloan-Kettering Cancer Center in New York, and colleagues reviewed the incidence of electrolyte abnormalities among a consecutive case series of 154 patients treated with cetuximab at their institution.

Of the 34 patients who had their magnesium levels measured at least once during cetuximab treatment, six had grade 3 hypomagnesemia and two had grade 4. The authors hypothesize that because EGFR is strongly expressed in the kidney--particularly where most of the magnesium is reabsorbed into the organ--blocking EGFR with cetuximab may interfere with magnesium transport. They suggest that if cetuximab-treated patients have symptoms of hypomagnesemia--fatigue, paresthesias (itching, burning, or tingling skin sensations), and low levels of calcium in the blood--then they should have their magnesium levels checked and, if low, receive magnesium supplementation.

Tie-1 significantly inhibits tumor progression in murine models

Thu, 11 Aug 2005 23:06:00 PST

( from http://www.rxpgnews.com ) Dyax Corp. (Nasdaq: DYAX) announced today its presentation at the Drug Discovery Technology Conference (Boston Convention Center), highlighting the Company's discovery that antibody targeting of Tie-1 leads to the inhibition of primary tumor growth in murine models.

The lead IgG antibody is derived from Dyax's proprietary human antibody phage display libraries. The therapeutic rationale for targeting Tie-1 (receptor tyrosine kinase) to inhibit tumor vascular development, and the results from the Company's preclinical studies, will be presented at 9:30 a.m. (ET) today by Clive R. Wood, Ph.D., Senior Vice President Discovery Research and Chief Scientific Officer of Dyax.

In vitro assays demonstrate that Dyax's lead antibody binds with high affinity to both human and murine endothelial cells that express Tie-1, and significantly inhibits both lung and colorectal tumor progression in mouse xenograft models. These data suggest that antibody-based targeting of Tie-1 offers a new mechanistic class of tumor angiogenesis inhibitor which is distinct from those targeting the vascular endothelial cell growth factor (VEGF) pathway.

Dyax's progress to date with Tie-1 has been made through a research collaboration between the Company and Dr. Kari Alitalo, a leading authority in the area of angiogenesis and cancer research, based at the University of Helsinki, Finland. In 2001, Dyax obtained exclusive rights from Licentia Ltd., technology transfer company associated with the University, to develop antibody therapeutics and/or diagnostic products against Tie-1. Dyax has in-licensed all relevant antibody intellectual property from Licentia, and has since developed its own patent estate in this area.

Commenting for Dyax, Dr. Wood said, "This has been a very productive collaboration between Dr. Alitalo's laboratory and Dyax Discovery Research. It represents a breakthrough for our understanding of Tie-1 and its role in tumor therapy. I am most excited about the potential clinical advantages of inhibiting tumor growth by targeting Tie-1 and the possible combination therapies that this new approach may offer."

Henry E. Blair, Chairman, President and CEO of Dyax added, "It has been a goal at Dyax to expand into oncology as we continue to advance our clinical programs in inflammation. In addition, we have been focused on isolating high quality antibodies from our libraries for formal development as we build our product pipeline. The discovery of this lead antibody against Tie-1 demonstrates success on both fronts."

Orphan Drug Application Filed for NOV-002 for Treating Refractory Ovarian Cancer

Fri, 17 Jun 2005 09:56:00 PST

( from http://www.rxpgnews.com ) Novelos Therapeutics, Inc. (OTC BB: NVLT), a biotech company focusing on oxidized glutathione for use in fighting cancer and hepatitis, today announced that it has filed an orphan drug application with the U.S. FDA for the Company's lead compound, NOV-002. The application focuses on the investigation of combination therapy of NOV-002 with standard chemotherapy for treating refractory (chemotherapy resistant) ovarian cancer. A response from the FDA is expected by mid August.

In the U.S., an orphan drug designation may be granted to drugs that treat rare life-threatening diseases that affect less than 200,000 U.S. persons. Such designation provides a company with seven years of marketing exclusivity along with regulatory assistance and reduced fees.

Refractory ovarian cancer patients -- those who do not respond to chemotherapy -- have a very poor prognosis because they are faced with inadequate therapeutic options. Response rates from second-line treatments, such as doxorubicin and topotecan, are typically less than 12%; re-exposure to cisplatin-based treatment will typically have less than 15% response rate.*

In Russian clinical studies, NOV-002 has sensitized previously resistant ovarian cancers, substantially raising the patient response rate to chemotherapy treatment.

In 2005, ovarian cancer is expected to be diagnosed in approximately 22,220 U.S. women, and be responsible for 16,210 deaths. Standard first-line treatment for ovarian cancer patients is carboplatin and paclitaxel chemotherapy combination. Doxorubicin (Doxil) and topotecan (Hycamtin) alternate as second- and third-line chemotherapy treatments.*

Treating 'chemobrain' by using dexmethyphenidate (d-MPH)

Wed, 08 Jun 2005 13:00:00 PST

( from http://www.rxpgnews.com ) Patients who take medication for cancer often find themselves with a new problem when their treatment ends.
It's called "chemobrain," a common consequence of chemotherapy that causes memory problems, confusion and difficulty in concentrating.

Symptoms of chemobrain can also include lack of focus, inability to organize daily activities, mental confusion, memory loss and decreased mental clarity.

It's estimated that chemobrain occurs in as many as 99 percent of breast and ovarian cancer patients receiving chemotherapy or radiation treatments. Sixty-one percent of these patients continue to experience fatigue and memory problems long after their cancer treatment has stopped.

Now, researchers led by the University of Cincinnati's (UC) Elyse Lower, MD, report a possible new treatment for the problem using the drug dexmethyphenidate (d-MPH).

Dr. Lower, professor of hematology/oncology at UC College of Medicine, recently described the encouraging results of a 14-month, multi-center, Phase 2 study of d-MPH to the annual meeting of the American Society of Clinical Oncology.

The 154 cancer survivors at 21 medical centers showed significant reduction in fatigue and improvement in memory when treated with dosages of 10 mg to 50 mg of d-MPH per day, Dr. Lower said, when compared with a control group receiving a placebo.

All the patients, who had a median age of 53 years, had completed at least four cycles of chemotherapy at least two months before the study began. Ninety percent of them were female (76 percent with breast cancer and 14 percent with ovarian cancer), 79 percent were white and 9 percent were African-American.

"The study showed that up to 50 mg a day of d-MPH is safe and effective for relieving chemobrain in adult cancer patients," said Dr. Lower, "and it should be considered as a treatment."

One of the study participants, Marilyn Metz, had undergone radiation and chemotherapy in 2001 to treat breast cancer.

"I couldn't concentrate or focus long enough to finish most tasks," she said. "I would start projects, but couldn't concentrate, and often left them unfinished."

It got so bad that Metz found it difficult to talk to strangers on the phone.

"I wouldn't be able to think of a key word in a sentence," she said. "I felt like the word was in back of my brain. I just couldn't drag it forward quickly enough."

Before receiving treatment for breast cancer, Metz said, she had read about possible side effects such as losing hair, but did not read anything about chemobrain.

After talking to Dr. Lower, she decided to participate in the study.

"What's the good of being successfully treated for breast cancer if your brain isn't working right?" she asked.

"I appreciate the chemotherapy and radiation killing the cancer cells, and would take it again to continue living," Metz added. "I am even more thankful that new treatments are being found to treat the fatigue and other side effects of chemobrain."

After treatment with d-MPH, she added, "I can think more clearly and have more energy--but I'm still able to take naps in the afternoon, if I feel the need."

"This medication has really helped me," Metz said. "I feel like my brain capacity is back to normal."

All participants in this trial were offered the real medication free after the double-blinded trial had ended. Metz participated in the control group and began using d-MPH following the study.

A bioadhesive miconazole tablet is an effective way to treat oropharyngeal candidiasis

Tue, 07 Jun 2005 12:01:00 PST

( from http://www.rxpgnews.com ) A bioadhesive tablet containing the antifungal drug miconazole is an effective and convenient means of treating oropharyngeal candidiasis, which is the most frequently occurring infection in head and neck cancer patients undergoing radiation therapy, scientists report today at the 2nd ESMO Scientific & Educational Conference (ESEC) in Budapest, Hungary.

Dr. Rene-Jean Bensadoun from Centre Antoine Lacassagne in Nice, and international colleagues, studied patients in 36 centers who had completed radiotherapy for head and neck cancer and had oropharyngeal candidiasis confirmed by examination or fungal culture.

One group of 141 patients were given daily a bioadhesive tablet containing 50mg of miconazole, developed by BioAlliance Pharma, a French biopharmaceutical company, the other 141 patients received a mouth gel (MBG) containing 125mg of miconazole four times daily for 14 days.

"We found that the daily bioadhesive buccal tablet achieved the same efficacy as the gel, but required one-tenth as much miconazole, and could be given on a much more convenient schedule," Dr. Bensadoun said.

"Patients currently need to apply the gel four times a day, which is disruptive to their day and increases the risk that they will miss treatments and suffer the discomfort of candidiasis for a longer period of time."

"While oropharyngeal candidiasis is perhaps not a dangerous infection, it is unpleasant, and anything we can do as oncologists to improve the quality of life of cancer patients is a positive thing."

"Head and neck cancer patients suffer not only from their disease, but experience many acute and chronic side-effects due to treatment", comments Dr. Dirk Schrijvers from the Department of Medical Oncology of the ZNA Middelheim, Antwerp, Belgium. Everything that can improve the quality of life of these patients during and after treatment will have an impact on treatment compliance and disease outcome. By providing a simpler way of controlling oral candidiasis, patient compliance may increase.

p53-based Targets as Novel Cancer Treatment Strategies

Fri, 03 Jun 2005 10:22:00 PST

( from http://www.rxpgnews.com ) ADVEXIN(R) and INGN 225, investigational cancer therapies currently being evaluated in Phase 3 and Phase 2 trials, respectively, by Introgen Therapeutics, Inc. , were highlighted today in a special session, titled "The Clinical Trial Data on Ad-p53 Gene Therapy of Cancer" at the American Society of Gene Therapy 8th Annual Meeting (ASGT).

Introgen's collaborators, Jack A. Roth, M.D., Chairman and Professor of the Department of Thoracic and Cardiovascular Surgery at The University of Texas M. D. Anderson Cancer Center, and Dmitry Gabrilovich, M.D., Associate Professor of Oncology at the H. Lee Moffitt Cancer Center reviewed the data generated to date with these investigational therapies.

The special session titled "The Clinical Trial Data on Ad-p53 Gene Therapy of Cancer" was co-chaired by Drs. James S. Norris, Medical University of South Carolina, and Helen E. Heslop, . Joining Drs. Roth and Gabrilovich was Dr. Yongsong Guan of Sichuan University.

"The presented data emphasize the broad potential application of ADVEXIN as a monotherapy and in combination with other treatments in the therapy of numerous cancers in a wide range of clinical settings," said Robert E. Sobol, M.D., senior vice president, Medical and Scientific Affairs at Introgen. "This special session at ASGT also underscores the ongoing interest in the p53 tumor suppressor gene as a novel cancer therapy. With ADVEXIN now in Phase 3 trials, we are closer than ever to realizing the potential of this key tumor suppressor gene in the treatment of cancer. Additionally, our clinical data with INGN 225, a therapeutic cancer vaccine utilizing ADVEXIN-treated immune cells, further demonstrates the broad utility of p53-based targets combined with standard therapies in the development of novel cancer treatment strategies."

Dr. Roth presented data from several ADVEXIN clinical studies including head and neck, lung, breast and new data in esophageal cancer.

ADVEXIN Provides Symptomatic Improvement in Esophageal Cancer Patients

The results of a Phase I/II trial of ADVEXIN in esophageal cancer refractory to chemotherapy and radiation were reported for the first time at ASGT by Dr. Roth. The trial was performed by Drs. Takenori Ochiai, Hideaki Shimada and colleagues from Chiba University in Japan. In this study, 30 percent of the patients (3/10) had significant symptomatic improvement in swallowing after ADVEXIN therapy. In addition, the median survival of the ADVEXIN treated patients was approximately 12 months which compared favorably to historical controls from that institution in which survival of less than 10 months was observed for patients who did not respond to these standard treatments. Six patients (60 percent) were still alive 1 year after beginning therapy.

ADVEXIN Trials in Head and Neck, Breast and Lung Cancers

In addition to these new findings regarding ADVEXIN in esophageal cancer, previously reported results of ADVEXIN as monotherapy in recurrent head and neck cancer and as part of initial therapy in combination with chemotherapy or radiation for breast and lung cancer were also presented.

The results of multi-national, multi-site Phase 2 clinical trials of ADVEXIN therapy in 217 patients with recurrent squamous cell cancer of the head and neck were reviewed. Patients treated with higher doses of ADVEXIN had a statistically significant increase in median survival compared to patients treated with lower doses (243 vs. 119 days). A subpopulation of patients participating in these trials had certain defining prognostic, medical and biological characteristics that represent refined targeting of ADVEXIN therapy. Analysis of the data from this patient subpopulation showed that the objective response rate (complete responses and partial responses with greater than 50% tumor reduction) was over 15%. Patients achieving disease control also showed clinical benefit reflected by either lack of progression and/or improvement in disease related morbidity.

In the breast cancer study of 12 women with very large tumors, the combination of ADVEXIN and chemotherapy resulted in objective clinical responses with greater than 50 percent tumor reduction in all patients and the ability to completely remove all of the tumors surgically. These data are better than the expected results with chemotherapy alone. Similarly, in 19 non-small cell lung cancer patients, combined ADVEXIN and radiation treatment resulted in 63 percent biopsy-proven complete responses at 3 months that is approximately 4 times the expected rate with radiotherapy alone.

INGN 225 in Patients with Advanced Small Cell Lung Cancer

Dr. Gabrilovich presented data from the ongoing Phase 2 trial of INGN 225 in patients with advanced small cell lung cancer previously treated with chemotherapy. These findings were presented in May 2005 at the American Society of Clinical Oncology Annual Meeting. These data show that the vaccine was well tolerated, with no appreciable INGN 225 related toxicity in any of the treated patients. After vaccine therapy, eighteen patients with progressive disease were treated with second-line chemotherapy. To date, 12 patients (66.7 percent) had objective responses or tumor reduction greater than 50 percent. Historically the expected objective response rate in these patients is between 20 and 30 percent. There was a statistically significant correlation between the development of a p53 immunological response to vaccination and objective responses to second line chemotherapy.

About ADVEXIN

ADVEXIN supplies the tumor suppressor p53 protein in very high concentrations in cancer tissue to selectively kill cancer cells. p53 is a normal constituent of cells and is known as a tumor suppressor because it inhibits the growth of tumor cells. One of the major roles of this protein is to eliminate cancerous cells by recognizing when DNA has been damaged by mutations or therapy and stopping cell growth. If the cell is damaged beyond repair, p53 activates programmed cell death pathways (apoptosis) to prevent the growth and propagation of cells with DNA damage.

There are two Phase 3 trials of ADVEXIN therapy currently underway in recurrent squamous cell cancer of the head and neck (SCCHN). Introgen has received FDA Fast Track designation for ADVEXIN therapy and ADVEXIN has been designated as an Orphan Drug for the treatment of head and neck cancer under the Orphan Drug Act.

About INGN 225

INGN 225 is a personalized therapeutic vaccine consisting of a cancer patient's dendritic cells, a type of immune cell, treated with an adenovector carrying the human p53 gene (Ad-p53). As a personalized vaccine, a small blood sample is obtained from a cancer patient and used as a source of dendritic cells, a type of cell that play a critical role in activating T- cells to attack cancerous or virally infected cells. An adenoviral vector is then used to deliver the p53 gene to the purified dendritic cells. When these modified dendritic cells are returned to the patient's body, they activate the patient's T-cells to seek out and destroy cancer cells that express p53.

Tarvacin Plus Docetaxel Significantly Inhibits Breast Tumor Growth

Fri, 27 May 2005 18:03:00 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, Inc. , today announced that a research article titled "A Monoclonal Antibody that Binds Anionic Phospholipids on Tumor Blood Vessels Enhances the Antitumor Effect of Docetaxel on Human Breast Tumors in Mice" was published in the May 15 issue of Cancer Research.

The published report shows that 3G4 (a murine equivalent of the company's Tarvacin(TM) monoclonal antibody) in combination with docetaxel results in a 93% inhibition of human breast cancer growth in mouse models.

The researchers found that docetaxel increases the exposure of the 3G4 target on tumor blood vessels but not healthy tissue. Patient enrollment in a Tarvacin(TM) Phase 1 clinical trial for the treatment of all solid tumors, including breast cancer, is expected to commence this month at three clinical sites.

"Our results suggest that Tarvacin(TM) holds promise to be a therapeutic agent that can significantly improve current breast cancer therapy," said Dr. Xianming Huang, the lead author of the report. "While docetaxel is the most important cytotoxic drug currently available for breast cancer, its maximum dose is limited by its toxicity, leaving a pressing need for combination therapies that improve its efficacy without exacerbating its toxicity."

Dr. Huang is an assistant professor of pharmacology in Dr. Philip Thorpe's laboratory at the University of Texas Southwestern Medical Center at Dallas. Further pre-clinical studies studying the potential of Tarvacin(TM) in the treatment of drug-resistant breast cancer and in breast cancer metastasis are ongoing at UT Southwestern under a grant by the Susan G. Komen Breast Cancer Foundation and a sponsored research agreement with Peregrine Pharmaceuticals.

In the study, treatment of mice with 3G4 plus docetaxel inhibited tumor growth by 93% as compared with 50% and 70% for 3G4 and docetaxel, respectively, when used as single agents. Furthermore, treatment of mice bearing disseminated breast cancer with the same combination reduced the average number of tumor colonies in the lungs by 93% and half of the animals did not develop tumors at all. Docetaxel and 3G4 inhibited lung colonization by 78% and 82% respectively when given as single agents. In both models, the combination therapy was no more toxic to the mice than docetaxel alone.

About Tarvacin(TM)

Tarvacin(TM) is part of Peregrine Pharmaceutical's Anti-Phospholipid Therapy platform, which binds directly to tumor blood vessels to inhibit tumor growth and development. Tarvacin(TM) is a chimeric monoclonal antibody that binds to the phospholipid, phosphatidylserine. Tarvacin(TM) was initially discovered by researchers at UT Southwestern Medical Center at Dallas, who have worked closely with Peregrine to explore the potential activity and safety of Tarvacin(TM) as a treatment for cancer. Peregrine has a sponsored research agreement with researchers at UT Southwestern to study the use of Tarvacin(TM) and its parent antibody for the treatment of cancer and viral diseases.

Capecitabine as a Convenient Oral Treatment for Colon Cancer Patients

Mon, 23 May 2005 10:28:00 PST

( from http://www.rxpgnews.com ) Data presented this week further strengthens the wealth of evidence showing that Xeloda(R) (capecitabine), an innovative oral chemotherapy, should replace the current standard treatment of intravenous 5-fluorouracil/leucovorin (i.v. 5-FU/LV) for colon cancer patients in the adjuvant (post-surgery) setting. In March 2005, Roche received approval from the European authorities for Xeloda to be used as a post-surgery treatment in colon cancer patients.

The data, in the adjuvant setting, presented at ASCO demonstrate that Xeloda provides a unique treatment option with unsurpassed benefits for colon cancer patients. Specifically it offers patients:

* Proven efficacy: confirmed to be at least as effective as standard chemotherapy

* A prolonged cancer-free life: relapse-free survival rates are significantly higher with Xeloda than with standard intravenous chemotherapy. There is a strong trend towards disease-free survival with Xeloda

* Tolerability: less serious and more manageable side effects reported with Xeloda than with standard chemotherapy

* Cost-effectiveness: on average, with Xeloda a patient only needs 8 hospital visits compared to 30 if treated with standard chemotherapy1

* Convenience: as Xeloda is a tablet, patients can take it in the comfort of their own home and not have to travel to cancer centres for treatment

"Being diagnosed with colon cancer is a traumatic, life-changing experience that you cannot prepare for," said Andy Griffin, a colon cancer patient based in the UK. "Like many colon cancer patients I dreaded the idea of undergoing chemotherapy in hospital but my experience with Xeloda was very positive. It is an oral medication and I could take it at home. Xeloda gave me the freedom to continue working and maintain a normal life during this difficult time."

"This new data confirming that Xeloda should replace standard 5FU/LV chemotherapy is exciting news for patients and their doctors alike," Professor Chris Twelves, University of Leeds and Tom Connors Cancer Research Centre, Bradford, UK. "It gives colon cancer patients the freedom to use an effective, tolerable, and convenient oral treatment that is as at least effective as traditional intravenous chemotherapy but has fewer side effects and avoids the burden of frequent and expensive hospital visits."

LErafAON-ETU : a Liposome Entrapped c-raf Antisense Oligonucleotide for Advanced Cancer

Sat, 21 May 2005 10:42:00 PST

( from http://www.rxpgnews.com ) NeoPharm (Nasdaq:NEOL) announced that preliminary Phase I clinical trial data for the Company's NeoLipid(TM) compound LErafAON-ETU was published in the American Society for Clinical Oncology (ASCO) Annual Meeting Proceedings. ASCO was held May 13-17, 2005 in Orlando, Florida.

LErafAON-ETU - ASCO Meeting Proceedings - Abstract #3214

LErafAON-ETU is NeoPharm's easy-to-use liposomal formulation of an antisense oligonucleotide (AON) complementary to the c-raf mRNA sequence, which mediates tumor cell growth.

This drug formulation utilizes the Company's NeoPhectin(TM) transfection reagent which consists of a novel, positively charged, synthetic cardiolipin (PCL-2) and appears to eliminate the need for extensive phosphorothioate modification of the AON which can be associated with toxicity.

This reagent also has potential use in the delivery of nucleic acids and siRNA molecules.

"The emerging technology of the liposome formulation used for LErafAON-ETU in this study represents an opportunity for potentially improving the delivery of novel cancer therapies," stated Michael Gordon, MD, Associate Professor of Medicine - University of Arizona College of Medicine, Associate Director-Arizona Cancer Center-Greater Phoenix Area and the Investigator on the NeoPharm Phase I LErafAON-ETU Clinical Study.

The published abstract entitled, "Phase I Study of LErafAON-ETU, an Easy-To-Use Formulation of Liposome Entrapped c-raf Antisense Oligonucleotide, in Advanced Cancer Patients," highlights the successful initial clinical dosing of this novel drug formulation.

This Phase I dose-escalation study is designed to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of LErafAON-ETU in patients with advanced cancer. LErafAON-ETU is planned to be administered as an intravenous infusion once weekly for 3 consecutive weeks (a treatment cycle).

Patients are eligible to receive repeated treatment cycles until disease progression or unacceptable toxicity occurs. Dose levels of 7.5, 15, 30, 60, 120, 240, and 480 mg/m2 are planned, depending on the tolerability of LErafAON-ETU. Dose escalation is ongoing in this study.

Prostate Cancer Vaccine gets Special Protocol Assessment by FDA

Thu, 19 May 2005 09:35:00 PST

( from http://www.rxpgnews.com ) Cell Genesys, Inc. today announced that it has received a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA) for its second Phase 3 clinical trial of GVAX(R) vaccine for prostate cancer. The SPA is a process that allows for official FDA evaluation of a Phase 3 clinical trial and provides trial sponsors with binding written agreement that the design and analysis of the study are adequate to support a license application submission if the study is performed according to the SPA.

The company's first Phase 3 trial of GVAX(R) vaccine for prostate cancer was initiated in July 2004 and was also granted a SPA by the FDA.

"The SPAs for our two Phase 3 trials provide Cell Genesys with a well-defined pathway for regulatory submission for our lead product candidate, GVAX(R) vaccine for prostate cancer," stated Joseph J. Vallner, Ph.D., president and chief operating officer of Cell Genesys. "We look forward to initiating the second Phase 3 clinical trial of this GVAX(R) vaccine and hope that this product may one day benefit patients with prostate cancer."

Cell Genesys is currently planning two Phase 3 clinical trials of GVAX(R) vaccine for prostate cancer in hormone-refractory prostate cancer patients with radiologic evidence of metastatic disease. The first trial (VITAL-1 or Vaccine ImmunoTherapy with Allogeneic prostate cancer cell Lines) was initiated in July 2004 and is enrolling chemotherapy naive, asymptomatic patients without cancer-related pain and is comparing GVAX(R) vaccine to Taxotere(R) (docetaxel) chemotherapy plus prednisone with respect to a survival benefit. The trial is expected to enroll 600 patients and is designed to demonstrate a 33% improvement in the duration of survival for the GVAX(R) vaccine treatment arm. Cell Genesys received a SPA from the FDA for this trial in May 2004. Approximately 70 clinical trial sites in the Unites States are now open and patient accrual is ongoing.

The second trial (VITAL-2), for which the above-mentioned SPA was recently granted, is expected to begin in the near future and will enroll symptomatic patients with cancer-related pain and will compare GVAX(R) vaccine plus Taxotere(R) chemotherapy to Taxotere(R) chemotherapy plus prednisone with respect to a survival benefit. The VITAL-2 trial is also expected to enroll 600 patients and is designed to demonstrate a 33% improvement in the duration of survival for the GVAX(R) vaccine plus Taxotere(R) treatment arm. Both the VITAL-1 and VITAL-2 trials will enroll patients with all levels of Gleason scores (a measure of the aggressiveness of prostate cancer) including the highest risk patients.

The Company has conducted two Phase 2 trials of GVAX(R) vaccine for prostate cancer in patients with hormone refractory metastatic prostate cancer. At the May 2005 American Society for Clinical Oncology (ASCO) meeting, the company reported updated results from its second trial which indicated that in 22 patients receiving a dosing regimen comparable to that being used in Phase 3, the median survival has not yet been reached and will meet or exceed 24.1 months based on the median follow-up time in these patients. In September 2002, the company reported final results from its earlier trial of the vaccine in hormone refractory metastatic prostate cancer in which a median survival of 26.2 months was observed in 34 patients receiving vaccine treatment. These results compare favorably to the median survival of 18.9 months for hormone-refractory metastatic prostate cancer patients who were treated with Taxotere(R) plus prednisone based on a recently reported multi-center Phase 3 trial.

Clinical trials of GVAX(R) cancer vaccines are under way for multiple types of cancer including prostate cancer, lung cancer, pancreatic cancer, leukemia and myeloma. Cell Genesys' GVAX(R) cancer vaccines are whole-cell vaccines which are designed to stimulate an immune response against the patient's tumor. The vaccines are comprised of tumor cells that have been irradiated and genetically modified to secrete GM-CSF (granulocyte-macrophage colony stimulating factor), an immune stimulatory hormone which plays a key role in stimulating the body's immune response to vaccines.

Gliadel® Wafer Plus Temozolomide Show Promising Results in High Grade Malignant Glioma

Wed, 18 May 2005 09:58:00 PST

( from http://www.rxpgnews.com ) Guilford Pharmaceuticals Inc. today announced findings from a study of GLIADEL(R) Wafer (polifeprosan 20 with carmustine) and temozolomide used in combination to treat adult patients with newly diagnosed high grade malignant glioma. The data were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in Orlando, FL.

Results of the ongoing, Phase II, multi-center, single-arm trial show acceptable toxicities when combining the two chemotherapeutic agents, and suggest that the combination may be given safely to patients with initial high grade malignant glioma.

During the trial, patients underwent surgical resection followed by implantation of GLIADEL(R), a localized chemotherapy inserted directly into the resection cavity. Patients were then treated with oral daily temozolomide and standard radiotherapy, followed by up to 18 cycles of oral monthly temozolomide.

"This is a logical follow-up to the work of Stupp et al. (New England Journal of Medicine, March 10, 2005 Volume 352, No.10)," said Renato V. LaRocca, M.D., FACP of Kentuckiana Cancer Institute PLLC and Principal Investigator of the study. "GLIADEL(R) and temozolomide are the only FDA- approved treatments clinically proven to prolong survival in patients with newly diagnosed high grade malignant glioma. We are encouraged by the initial results."

The sequential use of the these agents is based on the concept that treatment with GLIADEL(R) provides local chemotherapy at a time when the residual tumor cells would be otherwise untreated, prior to the commencement of radiation and systemic chemotherapy.

A major question has been the safety of combining the two treatment approaches, and these data begin to address the issue. Side effects in the study were similar to those reported in the medical literature and from previous Phase III trials for each treatment, along with surgical resection and radiation therapy.

About GLIADEL(R) Wafer

GLIADEL(R) Wafer is the only marketed cancer treatment capable of delivering chemotherapy directly to the site of a brain tumor, bypassing the blood-brain barrier and minimizing drug exposure to other areas of the body. GLIADEL(R) Wafer is a small, white to off-white dime-sized wafer comprised of a biodegradable polymer (polifeprosan 20) incorporating 7.7 mg. of carmustine (BCNU), a chemotherapeutic agent usually administered intravenously to treat a malignant glioma. Up to eight GLIADEL(R) Wafers can be implanted in the cavity created when a surgeon removes a brain tumor. There, they slowly dissolve, releasing BCNU directly to the tumor site in high concentrations, while minimizing drug exposure to other areas of the body.

Important Information About GLIADEL(R) Wafer

GLIADEL(R) Wafer is indicated in newly diagnosed patients with high-grade malignant glioma as an adjunct to surgery and radiation. GLIADEL(R) Wafer is also indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.

The following four categories of adverse events are possibly related to treatment with GLIADEL(R) Wafer during initial resection.

Frequencies are listed of events that occurred in a randomized trial of GLIADEL(R) Wafer and placebo, respectively: seizure (33.3% vs 37.5%); brain edema (22.5% and 19.2%); healing abnormalities (15.8% vs 11.7%); and intracranial infection (5.0% vs 6.0%). The following three categories of adverse events are possibly related to treatment with GLIADEL(R) Wafer for recurrent disease. Frequencies are listed of events that occurred in a randomized trial of GLIADEL(R) Wafer and placebo, respectively: post-operative seizure (19% vs 19%); healing abnormalities (14% vs 5%); intracranial hypertension (4% vs 6%) and intracranial infection (4% vs 1%).

Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL(R) Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema.

Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL(R) Wafer, including one case leading to brain herniation. GLIADEL(R) Wafer contains carmustine and should not be given to patients who are allergic to carmustine. Carmustine can also cause fetal harm when administered to a pregnant woman.

The short and long-term toxicity profiles of GLIADEL(R) Wafer when given in conjunction with radiation or chemotherapy have not been fully explored.

Gemcitabine Based Regimens Improve Quality of Life in Non-Small Cell Lung Cancer

Wed, 18 May 2005 09:49:00 PST

( from http://www.rxpgnews.com ) Data presented today(1,2,3) from ongoing clinical trials show that therapies based on Eli Lilly and Company's (LLY) Gemzar(R) (gemcitabine, HCl) administered prior to surgery have a positive impact on survival, tumor shrinkage and quality of life among patients with early-stage non-small cell lung cancer (NSCLC).

Gemzar, which is approved in various countries for the treatment of lung, breast, pancreatic, bladder, ovarian and cervical cancers, is one of the most highly studied anti-cancer agents in the world and these findings add to the body of evidence of Gemzar's efficacy in another stage of lung cancer.

The study results, presented at the 41st annual meeting of the American Society of Clinical Oncology (ASCO), are part of the ongoing GINEST Project, which is a dual-clinical trial project evaluating the effectiveness of Gemzar in combination with other leading chemotherapy agents in the treatment of Stage I or II non-small cell lung cancer.

"Unfortunately, the risk of recurrence of lung cancer is a major problem even in early stages of the disease," said Richard Gralla, M.D., president of the New York Lung Cancer Alliance and a GINEST investigator. "Traditionally, treatment of Stage I or II non-small cell lung cancer has only involved surgery. The goal of administering these regimens prior to surgery is to treat any microscopic spread of disease and shrink the tumor to enhance the likelihood of surgical removal of the tumor. As we continue this project, we hope to learn which chemotherapy regimens produce the best results, and do so safely while maintaining or improving patients' quality of life."

Study Highlights

* Pre-operative therapy with Gemzar plus platinum or non-platinum agents was highly tolerable, allowing 77 percent of patients to proceed to surgical removal of the tumor; of these patients, 90 percent have had complete removal of their lung cancer. Treatment with Gemzar-based therapy also demonstrated a one-year survival rate of 74 percent in clinical study.(4)

* Pulmonary function testing (assessment of how well the lungs are working) and dyspnea scores (assessment of breathing difficulties) obtained pre- and post-chemotherapy to assess drug-induced injury to the lungs and effect on the ability to undergo surgery confirmed the safety of these regimens. Of the 62 patients evaluated, only two were unable to undergo surgery because of reduced lung function, and no patients experienced severe respiratory problems.(5)

* At six months after surgery, 78 percent of patients rated their quality of life as improved or stable.(6)

* Seven patients reported worsening of quality of life due to undergoing more than one operation and/or advancing to Stage III lung cancer. The decreased quality of life did not seem to be a result of the chemotherapy regimen.(7)

* The most common side effects were blood-related:

-- Twenty-four patients (30 percent) experienced Grade 3/4 leukopenia (an abnormal decrease in the number of white blood cells); and 8 patients (10 percent) experienced Grade 3/4 thrombocytopenia (a decrease in the number of platelets in the blood, resulting in the potential for increased bleeding and decreased ability for clotting).(8)

According to the World Health Organization, approximately 1.2 million people globally will be diagnosed with lung cancer this year.(9) It is the most lethal of all cancers. About 80 percent of all lung cancer diagnoses are of the non-small cell variety. As with any cancer, early detection and treatment of lung cancer provides the best hope for managing the disease effectively.

"Gemzar has a strong heritage in the treatment of advanced non-small cell lung cancer," said Coleman Obasaju, MD, U.S. oncology medical director at Lilly. "Gemzar's ability to demonstrate efficacy with a wide array of chemotherapeutic regimens makes it a cornerstone of lung cancer therapy."

GINEST Methods

Eighty-two patients with clinical Stage I (24 percent) and Stage II (76 percent) NSCLC were randomized and treated with chemotherapy prior to surgery. In the first trial, 54 patients were treated with either Gemzar 1000 mg plus carboplatin, or Gemzar 1000 mg plus paclitaxel 200 mg. In the second trial, 28 patients received the same regimen of Gemzar/carboplatin, or Gemzar 1000 mg plus cisplatin 75 mg. Each combination was given for three cycles every 21 days. In the quality of life evaluation, the analysis compares patient- determined quality of life ratings from baseline to 6 months after surgery (total 9-month evaluation period). This ongoing portion of the study includes 33 patients (48 percent male, 52 percent female) at an average age of 63, 94 percent of whom underwent surgery. Patients completed the Lung Cancer Symptom Scale (LCSS) (an instrument used to assess health-related quality of life in patients with lung cancer) at baseline and every three months after surgery.

Gemzar

Gemzar is one of the most widely studied treatments in the history of chemotherapy agents, and has been approved for use in more than 90 countries worldwide. It is the worldwide standard for care of pancreatic cancer and in many parts of the world for non-small cell lung, bladder and breast cancers.

Gemzar is approved in more than 60 countries as a single agent for the treatment of locally advanced or metastatic pancreatic cancer. It is also approved, in combination with Taxol(R) (paclitaxel), in more than 30 countries for the treatment of metastatic breast cancer. In most European countries, Gemzar is approved as a single agent or in combination with cisplatin for the treatment of advanced non-small cell lung cancer.

Gemzar, in combination with carboplatin, is approved in several European markets for the treatment of recurrent epithelial ovarian cancer. Most recently, Gemzar was approved in Mexico for cervical cancer, making it the first approval for this disease. Gemzar is a nucleoside analogue that interferes with the process of DNA production; thereby preventing cancer cells from replicating and thus slows or stops tumor growth.

Velafermin Shows Promising Results in Prevention of Chemotherapy Induced Oral mucositis

Wed, 18 May 2005 09:37:00 PST

( from http://www.rxpgnews.com ) CuraGen Corporation today announced that Michael W. Schuster, M.D., Principal Investigator, Professor of Clinical Medicine in the Division of Hematology/Oncology at the Weill Medical College of Cornell University, and Director of Stem Cell Transplantation at NewYork-Presbyterian Hospital/Weill Cornell Medical Center presented the final Phase I results for a single-dose of velafermin (CG53135) for the prevention of oral mucositis (OM) in patients receiving high dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (AHSCT) at the American Society of Clinical Oncology (ASCO) Annual Meeting in Orlando, FL.

The final results from this Phase I study suggest velafermin (CG53135) is well tolerated following intravenous administration with data supporting the Company's ongoing Phase II trial and strategy of investigating a single-dose of velafermin (CG53135) for the prevention of OM.

"Based on our experience with velafermin in Phase I, we are pleased to be taking part in the Phase II trial to evaluate this investigational drug for the prevention of OM," stated Michael W. Schuster, M.D. "Oral mucositis is a severe side effect that frequently occurs as a result of the high-dose chemotherapy administered to patients prior to bone marrow transplantation. Fibroblast growth factors, including velafermin, represent a new class of drugs that show promise for potentially avoiding or ameliorating OM and avoiding complications associated with this condition, such as pain and infection, and improving patients' quality of life."

"As we continue to advance velafermin through Phase II, we are pleased with the progress being made in the program and remain on track to complete this trial during the first half of 2006," stated Timothy M. Shannon, M.D., Executive Vice President of Research and Development and Chief Medical Officer at CuraGen. "In addition to exploring the efficacy of a single-dose of velafermin for the prevention of OM, we are also evaluating the safety of velafermin in a Phase I study for the treatment of active OM, specifically in patients who develop OM as a result of the chemotherapy they receive for the treatment of their cancer."

Data on 30 patients dosed with velafermin (CG53135) were presented in a poster entitled, "Phase I Trial of CG53135-05 (Velafermin) to Prevent Mucositis in Patients Undergoing High-dose Chemotherapy (HDCT) and Autologous Peripheral Blood Stem Cell Transplantation (PBSCT)." Primary objectives for the study were the evaluation of safety, tolerability, and pharmacokinetics following a single-dose of velafermin (CG53135). As a secondary objective, the study assessed the development of OM using the WHO OM assessment scale. Patients received a single-dose of 0.03, 0.1, 0.2, or 0.33 mg/kg velafermin (CG53135) administered intravenously one day after infusion of blood stem cells following high-dose chemotherapy.

Of the 30 patients (male = 21, female = 9) presented in this poster, the median age was 55 years (range 25-75) with diagnoses including multiple myeloma (n=16), non-Hodgkin's lymphoma (n=12), acute myelogenous leukemia (n=1) and desmoplasmic round cell tumor (n=1). High-dose chemotherapy conditioning regimens included high-dose melphalan (Mel 200), carboplatin and thiotepa, cyclophosphamide, carmustine, and etoposide, and busulfan and cyclophosphamide. No serious drug-related adverse events were noted following treatment with velafermin (CG53135). Mild to moderate reactions including nausea, vomiting, tachycardia, hypotension, chills, and fever were observed. Following administration of a single-dose of velafermin (CG53135), 22 of 30 patients (73%) did not develop severe grade 3 or 4 OM.

Based on results from Phase I, the 0.03, 0.1 and 0.2 mg/kg single doses of velafermin (CG53135) are currently being evaluated in a randomized, double- blind, placebo-controlled, multi-center Phase II clinical trial for the prevention of OM in approximately 200 patients receiving HDCT followed by AHSCT. This trial is expected to be complete during the first half of 2006.

Background on Velafermin (CG53135) and OM

Velafermin (CG53135), a novel fibroblast growth factor discovered by CuraGen that appears to promote both epithelial and mesenchymal cell proliferation, is currently being investigated for the prevention and treatment of OM, a side effect experienced by cancer patients undergoing chemotherapy or radiation therapy.

The disease is characterized by inflammation and ulceration of the tissue lining the mouth and throat, leading to bleeding, pain, and difficulty eating and drinking. OM is sometimes a cause for clinicians to interrupt patients' cancer treatment regimens, thus limiting the success of therapeutic plans. Velafermin (CG53135) is being investigated for the prevention of OM by being administered to patients before the onset of symptoms in order to decrease the incidence and duration of the disease.

Animal studies suggest that velafermin (CG53135) may also be effective for the treatment of OM when it is administered after the onset of early signs of OM in order to decrease the duration and progression to severe OM. An effective therapy for OM has the potential to treat debilitating symptoms, to allow cancer patients to better tolerate the appropriate doses of cancer treatment, and to decrease hospitalization time.

FDA Accepts Sorafenib into Pilot 1 Program

Wed, 04 May 2005 21:43:00 PST

( from http://www.rxpgnews.com ) Bayer Pharmaceuticals Corporation (NYSE: BAY - News) and Onyx Pharmaceuticals, Inc. (Nasdaq: ONXX - News) today announced that sorafenib (formerly BAY 43-9006) has been accepted into the U.S. Food and Drug Administration's (FDA) Pilot 1 Program for continuous marketing applications.

The Pilot 1 Program was designed for therapies that have been granted Fast Track status by the FDA and that have the potential to provide important therapeutic benefit over available therapy. Sorafenib was granted Fast Track status for metastatic renal cell carcinoma (RCC), or kidney cancer, in March 2004.

"Participating in the Pilot 1 Program offers Bayer and Onyx the opportunity to continue the productive dialogue that was established with the FDA at the beginning of this clinical program," said Wolfgang Plischke, Head of Bayer HealthCare's Pharmaceuticals Division. "We are preparing our New Drug Application (NDA) for submission in this indication and receiving Pilot 1 status facilitates the review process. Pending completion of the NDA filing, we hope to make this treatment available to patients in the first half of 2006 if approved by FDA."

As one of the Prescription Drug User Fee Act (PDUFA) goals, the Pilot 1 Program is intended to expedite the continuous marketing application (CMA) concept (known generally as a "Rolling NDA"). As part of the program, eligible applicants submit portions ("Reviewable Units") of an application before submitting the complete NDA. The FDA agrees to complete review of these sections within a specified period of time and to provide early feedback to the applicant. Under the Pilot 1 Program designation, the FDA is committed to completing the review of each of these sections on a six-month timeline.

About Sorafenib

Sorafenib, a novel investigational drug candidate, is the first oral multi-kinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature. In preclinical models, sorafenib targeted members of two classes of kinases known to be involved in both tumor cell proliferation (tumor growth) and tumor angiogenesis (tumor blood supply) - two important cancer growth activities. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, FLT-3 and RET.

IND Filed for CRA-024781, a Novel Histone Deacetylase Inhibitor

Tue, 03 May 2005 09:50:00 PST

( from http://www.rxpgnews.com ) Celera Genomics (NYSE:CRA), an Applera Corporation business, today announced that it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for CRA-024781, a novel histone deacetylase (HDAC) inhibitor. Pending clearance by the FDA, Celera Genomics plans to initiate Phase 1 clinical trials.

HDAC inhibitors target HDAC enzymes and inhibit the proliferation of cancer cells and induce cancer cell death, or apoptosis(1).

Celera Genomics recently reported data at the American Association for Cancer Research (AACR) meeting in April 2005, showing the efficacy of CRA-024781 as an HDAC inhibitor in xenograft cancer models.

In addition, it was demonstrated that the measurement of tubulin and histone acetylation can be used to monitor the pharmacodynamic effects of CRA-024781 in vivo.

Histone deacetylation is carried out by a family of related HDAC enzymes. Inhibition of these enzymes causes changes to chromatin structure and to gene expression patterns, which results in the inhibition of proliferation of cancer cells, and induction of apoptosis. Celera Genomics published the first three-dimensional structure of an HDAC enzyme in July 2004, and this information has been used to aid the design of a series of novel HDAC inhibitors.

"We're pleased with the progress we've made in advancing CRA-024781 through its preclinical experiments to this point," said Robert Booth, Ph.D., Chief Scientific Officer of Celera Genomics. "We anticipate that we will utilize the insights we have gained from the identification of potential biomarkers of efficacy to design and implement our clinical trials, the first of which is planned to assess the safety and pharmacokinetics of CRA-024781 in a dose escalation study, at a projected cost of less than $3 million."

"Today's accomplishment reflects Celera's successful transition from sequencing the human genome and selling data to focusing on the realization of downstream value in therapeutics and diagnostics," said Kathy Ordonez, President of Celera Genomics. "While the Online/Information Business was important to Celera Genomics in its initial years, it is no longer strategically relevant and has been a source of cash consumption, estimated to be approximately $7 million for fiscal 2005, since many of the subscriptions were prepaid."

"Celera Genomics now has three important strategic assets. First, our proteomics platform continues to yield novel cancer targets that have been the focus of several partnerships for drug discovery and development, allowing us to advance them cost effectively. Secondly, and with today's achievement of filing for an IND with the FDA, our small molecule capability and pipeline of compounds is now sufficiently mature to look to partner and capitalize on this asset. Finally, Celera Diagnostics, a 50-50 joint venture with Applied Biosystems, is generating substantial product sales and making important discoveries for incorporation into future new products," Ms Ordonez added. "With the anticipated discontinuation of the Online/Information Business, Celera Genomics is now in a position to focus its efforts on its most substantial opportunities while managing its use of cash."

Celera Genomics has another compound, a Cathepsin K inhibitor, in a Phase I clinical trial as a potential treatment for osteoporosis. This compound is partnered with Merck, and has been in clinical trials since July 2004. This followed a multi-year collaboration with Merck to develop small molecule inhibitors of Cathepsin K, which was initiated in November 1996.

IORT Increases Survival Rates in Advanced Rectal Cancer

Sun, 01 May 2005 09:24:00 PST

( from http://www.rxpgnews.com ) Intraop Medical Corporation (OTCBB:IOPM), manufacturer of the Mobetron(R), announced that according to research presented at a recent international meeting, intraoperative radiation therapy (IORT) increases survival rates in patients with advanced or recurrent rectal cancer.

IORT is a specialized treatment in which patients are given a dose of radiation therapy during surgery directly to the tumor site. IORT has proven to be a valuable adjunct therapy for treating many types of solid tumors.

In a presentation at the 4th International Society of IORT (or "ISIORT) meeting held in Miami, Florida March 17-19, 2005, Harm Rutten, Chief of Surgical Oncology and a Mobetron user from Catharina Zeikenhuis in Eindhoven, the Netherlands, reported the results of a study at Eindhoven using IORT for the treatment of advanced and recurrent rectal cancer.

Eindhoven has the largest single institutional experience with this disease in the world. The 5-year survival rate in 260 advanced rectal cancer patients was 60% compared with the expected 5-year survival of about 25% with conventional approaches.

For 160 recurrent rectal cancer patients, Dr. Rutten reported a 5-year survival rate of 37% compared with the 5-10% survival seen with conventional approaches. In the subgroup in which the surgeon achieved complete removal of the tumor, the 5-year survival rate with IORT for recurrent rectal cancer increased to 54%.

Umberto Veronesi, world-renowned breast surgeon and Director of the European Institute of Oncology in Milan, gave the keynote address, entitled "Evolution of Local Management Therapies for Invasive Breast Cancer."

He noted that preliminary data from a randomized controlled trial in progress under the auspices of the European Institute of Oncology suggest that, for suitably selected patients, a single treatment with IORT produces equivalent results as the conventional treatment for early stage breast cancer, while eliminating 5 weeks of post-surgical radiation treatments.

Dr. Veronesi cautioned that longer follow-up would be needed to confirm their findings. The European Institute plans a new trial for women who are also candidates for breast conserving therapy but who are at higher risk for recurrence or have more aggressive disease. This protocol, similar to ones presented at the meeting by the Mayo Clinic in Scottsdale Arizona (another Mobetron user) and the University of Salzburg, includes IORT at the time of breast surgery, followed by a shorter course of post-surgical radiation therapy treatments than is given with conventional management.

Other presentations at the meeting reported benefits for IORT treatment in a variety of tumor locations. These included sarcomas, pediatric cancers, recurrent gynecological cancer, pancreatic cancer and gallbladder cancer.

Attendees from 12 countries made over 60 oral and 12 poster presentations at this two-day, bi-annual meeting. Five Mobetron users gave nine of these presentations -- two on breast cancer, two on rectal cancer, one on lung cancer (mesothelioma), one on extremity sarcoma, one on kidney cancer, and two on the general usage of the Mobetron.

The Meeting was supported in part by an unrestricted educational grant from Intraop Medical Corporation.

IND Filed for XL820, a Novel Anticancer Compound

Tue, 26 Apr 2005 12:07:00 PST

( from http://www.rxpgnews.com ) Exelixis, Inc. (Nasdaq: EXEL - News) has submitted an investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA) for XL820. This novel small molecule anticancer compound potently inhibits receptor tyrosine kinases (RTKs) implicated in tumor proliferation and vascularization. XL820 is the fifth compound to advance in clinical development from Exelixis' internal drug discovery capabilities. Pending clearance by the FDA, Exelixis intends to initiate a Phase I clinical trial for XL820.

"I am very enthusiastic about the continued productivity of our R&D groups. We filed three INDs last year, and XL820 is the first of three anticipated INDs for this year. We believe these compounds are high quality and have the potential to provide substantial therapeutic benefit to patients in need," said George A. Scangos, Ph.D., president and chief executive officer of Exelixis. "Before the end of 2005, we anticipate having eight compounds in clinical development, each of which potentially represents an important therapeutic advance."

XL820 inhibits the VEGF receptor, KIT and the PDGF receptor, which are clinically validated targets implicated in a variety of human cancers. XL820 exhibits dose-dependent growth inhibition in models of breast carcinoma, gliomas and leukemia. In an animal model of more advanced malignancy, significant tumor regression was seen. In non-clinical studies, XL820 has shown good oral bioavailability and sustained inhibition of target RTKs in vivo following a single oral dose.

Spectrum Selective Kinase Inhibitor(TM) (SSKI) Program

Exelixis' SSKI Program is focused on the development of compounds that are optimized to specifically target kinases implicated in tumor cell proliferation and angiogenesis thereby providing the potential for more potent therapeutic effects. The company currently has three compounds in active Phase I trials, which are XL647, XL999 and XL880, that came out of this program. Exelixis anticipates that it will complete the Phase I trials for XL647 and XL999 in the second half of 2005 and to initiate broad Phase II trial programs for these compounds as soon as practicable thereafter. The Phase I trial for XL880 was initiated in March and is actively enrolling patients. Exelixis is continuing to expand its SSKI Program by advancing additional diverse, high-quality compounds into clinical development, including XL844 and XL184 for which IND filings are anticipated in the first half of 2005, and has also made progress on earlier-stage compounds that are part of the SSKI Program.

CoFactor : A Folate-Based Biomodulator Drug Starts Phase III Trial for the Treatment of Metastatic Colorectal Cancer

Tue, 26 Apr 2005 12:00:00 PST

( from http://www.rxpgnews.com ) ADVENTRX Pharmaceuticals, Inc. (AMEX:ANX) today announced that it has received clearance from the US Food and Drug Administration (FDA) under a Special Protocol Assessment (SPA) to initiate a Phase III pivotal clinical trial with CoFactor for the treatment of metastatic colorectal cancer. CoFactor is the Company's biomodulator designed to enhance the activity of the widely used cancer drug 5-fluorouracil (5-FU).

The US Phase III pivotal clinical trial will be a randomized, open label multi-center, parallel group, study of CoFactor as a first-line, combination therapy in patients with metastatic colorectal carcinoma. The two-arm study is expected to include approximately 600 patients, half of whom will be treated with CoFactor, 5-FU and bevacizumab (Avastin(TM)), compared with the other half of the patient population who will be treated with leucovorin, 5-FU and bevacizumab (Avastin(TM)). The primary end-point for this study is progression free survival (PFS), defined as the time from start of treatment to time of disease progression or death.

ADVENTRX recently received clearance in the UK to begin an international Phase IIb trial with CoFactor in metastatic colorectal cancer and plans to file in the first half of this year for clearance to initiate a EU-based Phase III CoFactor study in pancreatic cancer. Results from the Company's ongoing Phase II clinical trial using CoFactor and 5-FU for metastatic colorectal cancer are expected to be announced in Q2 2005.

About CoFactor

CoFactor is a folate-based biomodulator drug developed to enhance the activity of the widely used cancer chemotherapeutic, 5-FU. Clinical data from previous clinical trials in Europe have demonstrated clinical benefit and improved overall median survival in patients with advanced tumors, including colorectal, pancreatic and breast. In comparison to leucovorin, CoFactor creates more stable binding of the active form of 5-FU, FdUMP, to the target enzyme, thymidylate synthase (TS).

CoFactor bypasses the chemical pathway required by leucovorin to deliver the active form of folate, allowing 5-FU to work more effectively. This improves 5-FU performance and lowers toxicity. ADVENTRX is the exclusive licensee of this compound. More information on CoFactor can be found at http://www.adventrx.com/products/antic_cofactor.htm.

Role of 2-methoxyestradiol in Treating Various Types of Cancer

Thu, 21 Apr 2005 14:09:00 PST

( from http://www.rxpgnews.com ) EntreMed, Inc. today announced the results of multiple in vitro and in vivo preclinical studies confirming the mechanisms-of-action for 2-methoxyestradiol (2ME2 or Panzem(R)) in treating various types of cancer. The results from these studies, conducted by EntreMed researchers and their collaborators, were presented at the 96th Annual Meeting of the American Association for Cancer Research being held this week in Anaheim, California.

The antiproliferative and antiangiogenic activity of 2ME2 has been demonstrated previously in multiple preclinical models and in early clinical studies. Data from these studies have shown that 2ME2 disrupts interphase microtubules, down-regulates HIF-1alpha, inhibits de novo synthesis of HIF- 1alpha, and induces apoptosis.

New data presented at the AACR Annual Meeting further demonstrated that 2ME2 inhibits HIF-1alpha translation by preventing localization of HIF-1alpha mRNA complexes with depolymerized microtubules.

Results from a second study showed that 2ME2-treated cancer cells depolymerized microtubules in a dose- dependent manner, while 2ME2 resistant cells with acquired tubulin mutations were unaffected.

Taken together, these studies show a close correlation between the antitubulin properties of 2ME2 and its antiproliferative effects. Furthermore, 2ME2 resistance is the result of tubulin mutations, rather than multi-drug-resistance (MDR) mechanisms.

Paraskevi Giannakakou, Ph.D., Assistant Professor of Hematology, Oncology and Pharmacology, Winship Cancer Center, Emory University School of Medicine and author on both studies commented, "Recent mechanistic studies from our laboratory have shown that 2ME2 depolymerizes microtubules resulting in potent inhibition of the transcription factor HIF-1alpha. We have also developed a 2ME2-resistant ovarian carcinoma model with an acquired tubulin mutation, which blocks 2ME2's ability to bind to tubulin and down-regulate HIF-1alpha. Since acquired drug resistance poses a major obstacle for the successful treatment of cancer patients, the 2ME2 resistance model will help facilitate future 2ME2 clinical trials and guide the discovery of new 2ME2 analogs with activity against drug-resistant cancer cells."

Results from a separate preclinical study demonstrated that 2ME2 induced apoptosis in human pancreatic and gastric cancer cells that were either chemosensitive or resistant (MDR) to conventional chemotherapeutics. MDR- negative cells were up to 10-fold more resistant than chemosensitive pancreatic and gastric cells, while MDR-positive cells were up to 1000-fold more resistant to cytotoxic drugs such as paclitaxel and cisplatin. In all cases, pancreatic and gastric cells were highly sensitive to 2ME2 and showed strong growth inhibition.

In addition, the number of apoptotic chemoresistant cells increased by 3-8 fold over chemosensitive pancreatic and gastric cancer cells. These findings support the potential use of 2ME2 even when chemoresistance occurs or as rescue therapy following resistance to chemotherapeutic agents.

In a separate preclinical colon cancer study, EntreMed collaborators demonstrated that the combination of 2ME2 and capecitabine (Xeloda) plus radiation therapy was highly effective in delaying colon tumor growth compared to capecitabine alone or in combination with radiation.

EntreMed scientists also reported on results of preclinical studies to determine the effect of schedule, route of administration and dose on the antitumor activity of Panzem(R) NCD in an orthotopic lung cancer model. Inhibition of pulmonary metastases was equivalent for several routes of administration; enhanced inhibition of tumor growth was observed with continuous vs. daily dosing; therapeutic response was similar with a fixed daily dose vs. a dose-intensification regimen; and antitumor activity improved with an increase in frequency from daily to four times daily administration.

The results of these studies indicate that the schedule of Panzem(R) NCD administration is a key determinant of antitumor activity.

Carolyn F. Sidor, M.D., EntreMed Vice President and Chief Medical Officer, commented on the presentations, "These studies provide further evidence of 2ME2's antiproliferative and antiangiogenic mechanisms of action. 2ME2 is a potent inhibitor of HIF-1alpha, and its down-regulation is closely associated with 2ME2's tubulin inhibitor properties.HIF-1alpha is over-expressed in more than 70% of human tumors and HIF-1alpha over-expression correlates with tumor aggressiveness, metastases and poor prognosis. In addition, HIF-1alpha is an upstream regulator of VEGF, and may affect a different or broader range of tumors than current VEGF inhibitors."

Dr. Sidor further commented, "We believe that 2ME2 has the potential to be a unique cancer therapy and may be particularly well-suited to attack tumors that are dependent on the proangiogenic activity of HIF-1alpha and VEGF for survival. Furthermore, 2ME2's safety profile and lack of MDR chemoresistance provide opportunities for combining it with conventional chemotherapies to increase their effectiveness while decreasing toxicity. EntreMed is currently evaluating 2ME2 formulations (Panzem(R) Capsules and Panzem(R) NCD) in Phase I and II clinical oncology studies, as well as preclinical studies of 2ME2 in inflammatory diseases such as RA."

FDA Gives ANDA Status to Vinorelbine for its Indication in Unresectable, Advanced Non Small Cell Lung Cancer

Wed, 20 Apr 2005 09:17:00 PST

( from http://www.rxpgnews.com ) American Pharmaceutical Partners, Inc. (Nasdaq: APPX - News) today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for the Abbreviated New Drug Application (ANDA) of Vinorelbine Tartrate Injection, 10 mg (base)/mL, the generic equivalent of GlaxoSmithKline's Navelbine®. According to IMS, sales of vinorelbine tartrate were approximately $61 million in 2004. The company expects to commence marketing this product in the near term.

Vinorelbine Tartrate is indicated as a single agent or in combination with cisplatin for the first line treatment of ambulatory patients with unresectable, advanced non small cell lung cancer (NSCLC). In patients with Stage IV NSCLC, vinorelbine tartrate is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, vinorelbine tartrate is indicated in combination with cisplatin.

"Vinorelbine represents APP's first ANDA approval in 2005 and is an important addition to our broad oncology product offering," said Al Heller, president and chief executive officer. "While the market for vinorelbine is competitive, we hope to leverage our position as a leading provider of generic oncology products."

Trilogy(TM) System for Image-Guided Radiosurgery is an Ultra-precise Treatment that Uses Real-Time X-ray Imaging Capabilities

Thu, 07 Apr 2005 18:14:00 PST

( from http://www.rxpgnews.com ) Providence Medical Center in Kansas City has become the first cancer treatment center in the Central U.S. to use the new Trilogy(TM) system from Varian Medical Systems (NYSE: VAR - News) for image-guided radiosurgery (IGRS), an ultra-precise treatment that uses new, real-time X-ray imaging capabilities to target cancer and neurological lesions.

The Providence physicians used the new Trilogy system during its first six weeks of operation to treat six patients with image-guided radiosurgery. The patients range in age from 40 to 67, and were treated for a broad range of conditions, including: brain metastases (in a lung cancer and a melanoma cancer patient), acoustic neuroma, arteriovenous malformation, glioblastoma, and a metastatic lesion in the sternum, which appeared in a patient being treated for squamous cell cancer of the tonsil.

"This state-of-the-art system enables us to treat patients with the most advanced radiotherapy techniques, using the most clinically efficient processes in the world," said Terry Jett, director of Radiation Oncology and Rehabilitation Services. "It provides the most versatile and highly targeted treatments using image-guided radiation therapy."

"This new technology offers hope and treatment to patients who might not have other options. It helps protect healthy brain or organ tissues. In the case of head and neck tumors, for example, we can target a tumor while preserving the patient's ability to talk and swallow," said Frank Holladay, M.D., a board-certified neurosurgeon on the Providence Medical Staff.

At the core of Providence's system is Varian's high-powered Trilogy medical linear accelerator, a machine that rotates around the patient to deliver radiation beams from many angles. The system is able to concentrate radiation doses on the tumor while protecting surrounding healthy tissue.

To enhance treatment precision, the Trilogy accelerator is equipped with a multi-leaf collimator that shapes beams to match the shape of the tumor, and an On-Board Imager(TM) device for fast, accurate, real-time tumor tracking and automated patient positioning.

"The Trilogy system is optimized for delivering image-guided radiotherapy and radiosurgery," said Dow Wilson, president of Varian's Oncology Systems business. "Its fully-robotic imaging system enables clinicians to position patients for treatment with sub-millimeter accuracy, and to accurately track and adjust for tumor movements at the moment of treatment."

Radiosurgical Approaches to Treatment

In addition to more conventional approaches to radiotherapy, the Trilogy linear accelerator can be used to deliver radiosurgery, which involves delivering higher doses of radiation to tiny areas over a short period of time. Instead of a patient undergoing invasive surgery, fractionated radiosurgery delivers high-intensity radiation over a limited number of treatment sessions.

Image-guided radiosurgery (IGRS) involves delivering precisely focused, high-energy radiation to a localized area of the brain in a single treatment session. It can be used to treat many types of benign and malignant brain tumors, as well as arteriovenous malformations and trigeminal neuralgia. Radiosurgery has been shown to be beneficial for cancer treatment in other areas of the body, such as in the breast, liver, and pancreas.

"Radiation therapy is used today in more than half of all cancer treatments due to its unique clinical advantages, and it is becoming steadily more effective with new technologies that permit ultra-precise dose delivery," said Lori Lindstrom, M.D., a board-certified radiation oncologist on the Providence Medical Staff. "With this new system, we have the potential to substantially improve cancer treatment outcomes by doing a better job of protecting healthy tissue while delivering more powerful radiation doses to the tumor."

"Trilogy is a cost-effective, versatile tool that can be used by both neurosurgeons and radiation oncologists in a multitude of ways to meet the individual treatment needs of patients with widely varying conditions," said Richard Levy, CEO of Varian Medical Systems. "For about half the cost, this machine takes the place of two machines and for the first time makes these advanced treatment techniques affordable for many community hospitals and their patients."

Trabectedin for the Treatment of Relapsed Ovarian Cancer Starts Phase III Trial

Mon, 04 Apr 2005 16:33:00 PST

( from http://www.rxpgnews.com ) PharmaMar today announced that, in collaboration with its partner Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), a pivotal, international, multicentre Phase III clinical trial in ovarian cancer patients has been initiated with YONDELIS(R) (trabectedin).

This Phase III study compares monotherapy liposomal doxorubicin, a Johnson & Johnson product(x) known as CAELYX(R) in Europe, and DOXIL(R) (doxorubicin HCI liposome injection) in the US, to a combination of YONDELIS and CAELYX (DOXIL) in ovarian cancer patients who have relapsed after receiving standard first-line chemotherapy. This randomised study will enrol 650 patients in 110 hospitals across 16 countries (including the US, Europe, Asia and South America).

The primary objective is to test the hypothesis that combination therapy with YONDELIS and DOXIL/CAELYX improves progression-free and overall survival in women with relapsed ovarian cancer . There also will be complementary pharmacogenomic studies to improve knowledge of ovarian cancer biology and help in the selection of patients who will benefit most from the drug combination.

The study protocol was reviewed by the American regulatory agency, the US Food and Drug Administration (US FDA), through the special protocol assessment (SPA) process. The SPA procedure allows sponsors to obtain official written guidance from the FDA on pivotal Phase III clinical trials .

This study also was reviewed by the European regulatory agency, the European Medicines Evaluation Agency (EMEA), through a similar process called Protocol Assistance (PA).

"PharmaMar and J&JPRD are committed to developing YONDELIS expeditiously to enable it to be considered for the treatment of relapsed ovarian cancer patients who currently are considered to be incurable," said Dr. Miguel Ãngel Izquierdo, Director of Clinical Development at PharmaMar.

"There is a need to offer additional treatment options to help to control this disease, improve the quality of life and increase patient survival. Based on data from Phase II trials with YONDELIS as a monotherapy in relapsed ovarian cancer patients, and in Phase I trials with YONDELIS in combination with CAELYX (DOXIL), we believe we may be able to provide a new option to these patients."

In previous Phase II studies, YONDELIS demonstrated activity in ovarian cancer patients who had relapsed after standard first-line treatment. YONDELIS indicated a response rate, a significant reduction in the tumour, in those patients of up to 43%(1).

Liposomal doxorubicin (CAELYX(R)/DOXIL(R)) already has been approved for this therapeutic use in this patient population. As the combination of YONDELIS with CAELYX (DOXIL) also demonstrated activity and tolerability in a previous study(2), the studys theoretical premise is that the combination of two active drugs may improve the survival rate of the target patient population.

According to the American Cancer Society (ACS) in the United States and Western Europe, ovarian cancer represents 4% of all cancers among women and ranks fifth as a cause of female deaths from cancer. The death rate for this disease has not changed significantly in the last 50 years.

The median age of women with ovarian cancer is 60, although it may occur in younger women with a family history of the disease. Nearly 70% of women with epithelial ovarian cancer, the most common type of ovarian cancer, are not diagnosed until the disease is advanced. The 5-year survival rate for these women is only 15%-20%, whereas the 5-year survival rate for Stage I disease patients is nearly 90% and for Stage II disease patients is 70%.

In 2004, there were an estimated 25,580 new cases of ovarian cancer in the US, and more than 16,000 women died from the disease. Incidence in the European Union was about 48,000 new cases in 2004 and approximately 31,000 deaths (Globocan 2002, IARC, WHO). According to the World Health Organisation, the highest incidence rates occur in the United States, Canada, Scandinavia and Eastern Europe.

YONDELIS(R)

YONDELIS (trabectedin), is PharmaMars most advanced compound in development, and originally was isolated from the marine tunicate Ecteinascidia turbinata, but now is manufactured by chemical synthesis.

YONDELIS currently is being developed by PharmaMar in partnership with Johnson & Johnson Pharmaceutical Research & Development, L.L.C. PharmaMar will market YONDELIS in Europe (including Eastern Europe) while Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., will market it in the US, Ortho Biotech, a division of Janssen-Cilag, will market it in the rest of the world.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Ortho Biotech Products, L.P. and Tibotec Therapeutics all are part of the Johnson & Johnson Family of Companies, the worlds most comprehensive and broadly based manufacturer of health care products.

YONDELIS(R) currently is also in Phase II studies in soft tissue sarcoma (comparative pivotal trial) and for prostate cancer.

In clinical studies to date, YONDELIS has shown a good safety and tolerability profile. The most frequent side effect is neutropenia, which is reversible and controllable. A transient increase in transaminases also has been observed.

YONDELIS is a new chemical entity with unique multicomponent mechanism of action. It is the only chemotherapy agent that binds to the DNAs minor groove and bends towards the major groove, producing its therapeutic effect by interfering with various cell division processes.

(x) DOXIL is marketed in the United States by Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., and in Israel by Janssen-Cilag. Schering-Plough Corporation, under a licensing agreement, has exclusive rights to market this medication as CAELYX(R) throughout the rest of the world, excluding Japan.

MORAb-003 :A Humanized Monoclonal Antibody for Chemo-Refractory Ovarian Tumors Starts Phase I Study

Wed, 30 Mar 2005 09:32:00 PST

( from http://www.rxpgnews.com ) Morphotek, Inc. today announced that the United States Food and Drug Administration has accepted its Investigational New Drug (IND) Application for treatment of advanced ovarian
cancer with MORAb-003, a humanized monoclonal antibody. The Phase I clinical study is designed as an open label single dose escalation safety study in patients with chemo-refractive ovarian cancer.

MORAb-003 is a monoclonal antibody that has high specificity for a number of different cancers, including ovarian, breast, colorectal, lung, renal, and brain. In pre-clinical cancer models the antibody has demonstrated that it can efficiently kill chemo-refractory tumors and suppress growth in xenograft studies.

"An unmet medical need exists for patients with advanced, chemo-refractory ovarian cancer," stated Nicholas Nicolaides, President and Chief Executive Officer. "In pre-clinical studies MORAb-003 has been shown to be active
against chemo-refractory ovarian tumors. The antibody targets a receptor present at high density on cancer cells, and offers a very high degree of specificity for malignant tissues. We look forward to updating the progress of this antibody as it advances through clinical trials."

"This is the first of several antibodies in our product portfolio that the company plans on advancing into clinical development for cancer, inflammation and infectious diseases," added Philip M. Sass, Executive Vice President and Chief Operating Officer of Morphotek."We are in the late stages of development for a second monoclonal antibody,MORAb-009,which is an antibody that targets a high percentage of pancreatic cancers and other difficult to
treat malignancies. We will file an IND by the end of this year."

Ovarian cancer ranks fourth in cancer deaths among women, accounting for more deaths than any other cancer of the reproductive system (American Cancer Society).In 2005, it is estimated that there will be 22,220 new cases of ovarian cancer in the U.S. and approximately 16,000 women will die from the disease.Worldwide, more than 182,000 new patients will be diagnosed with this form of cancer (World Health Organization).

Cysmethynil : A New Anti-Cancer Compound that Blocks the Icmt Protein Activation

Mon, 28 Mar 2005 11:30:00 PST

( from http://www.rxpgnews.com ) Duke Comprehensive Cancer Center scientists have discovered a potential new drug that inhibits destructive cell signals that drive the growth of one-third of all cancers. The scientists showed they could block the growth of cultured colon cancer cells using this new compound, called cysmethynil.

Their finding, reported in the March 22, 2005, issue of Proceedings of the National Academy of Sciences, is the first step toward developing a new class of anti-cancer drugs that block the Icmt protein from activating uncontrolled cell growth, a hallmark of cancer, according to Patrick Casey, Ph.D. Casey is the study's senior investigator and Duke pharmacologist and cancer biologist.

Moreover, said Casey, their discovery is the first to emerge from the Duke Small Molecule Screening Facility, which houses a library of more than 13,000 compounds available for screening promising drugs with potential to fight cancer and other diseases. Using automated robotics, the facility provides the kind of drug discovery capability usually available only to pharmaceutical company scientists.

Duke's new facility is a finalist for one of six $9 million National Institutes of Health (NIH) grants that will create a national network of publicly accessible small molecule facilities and make them available to researchers nationwide.

Duke University has filed a patent application for cysmethynil, Casey said, and intends to shepherd it through the first steps of drug development by testing the compound in animal models of cancer.

The research was supported by grant from the NIH and a Howard Hughes Medical Institute predoctoral fellowship to Casey graduate student Ann M. Winter-Vann, the first author of the study.

"This is the first selective small molecule inhibitor of Icmt, a protein that has been shown to be an important player in keeping a cancer-causing gene called 'Ras' turned on inside cells," said Casey.

Ras is a normal genetic component of the cell, but mutations in the gene can cause it to become stuck in an "on" position, promoting uncontrolled cell growth. Mutations in Ras that permanently activate it have been found in half of all colon cancer and 90 percent of pancreatic cancers, among other cancers.

Casey and his colleagues in Duke's Department of Pharmacology and Cancer Biology have already discovered and developed another class of cancer drugs aimed at inhibiting the processing pathway --the prenylation pathway that regulates Ras.

Several years ago, Casey's laboratory was one of a handful to unravel how the prenylation pathway works. This accomplishment led pharmaceutical companies to test compounds that block another key player in the pathway, a protein called farnesyltransferase.

Blocking this protein inhibits Ras' ability to send growth-promoting signals inside cells. Several such compounds have shown promise in treating leukemias and lymphomas and are now under consideration for final approval by the U.S. Food and Drug Administration.

Since that time, Casey and his colleagues have been studying another key player in the pathway, the Icmt enzyme. Icmt adds a chemical tag called a "methyl group" to Ras. This methyl tag enables Ras to be directed to its final destination in the cell, from where it can send signals for unchecked growth.

"Ras needs to be at the plasma membrane in order to function," he said. "By preventing Icmt from adding a methyl group, we can effectively shut down Ras' ability to function, stopping it from sending signals for uncontrolled growth."

Initial experiments showed that knocking out the Icmt protein using genetic targeting also inhibited Ras, so the scientists decided to search for an effective and specific molecule that could inhibit Icmt function.

"We were looking for a small molecule that inhibited this enzyme specifically, without interfering with the normal regulation of the cell," said Casey. "What we found was a series of 30 structurally related molecules, and we selected the one with the highest potency that is cysmethynil."

Once the scientists had identified cysmethynil, they worked with Duke chemist Eric Toone and chemistry graduate student David Gooden to synthesize the molecule and verify its chemical structure. A search of the chemical literature turned up no previous description of the chemical, leading the scientists to believe they had discovered a new chemical compound with a unique biological function.

When the scientists tested the compound's ability to inhibit Ras function in living cells, they found it blocked the ability of colon cancer cells to grow independently in soft agar, a typical test of the cancerous
potential of cells.

"The next step is to test cysmethynil in animal models," said Casey. "We don't know how the compound will be metabolized in living animals, but we are encouraged by our initial results."

GTI-2040 : A Novel Antisense Drug Improves Efficacy of a Number of Chemotherapies

Tue, 22 Mar 2005 08:32:00 PST

( from http://www.rxpgnews.com ) Lorus Therapeutics Inc., a biopharmaceutical company specializing in the research, development and commercialization of pharmaceutical products and technologies for the management of cancer, today announced that its wholly owned subsidiary GeneSense Technologies Inc. has received notice from the European Patent Office of its intention to grant the GeneSense application for a patent of its novel antisense drug GTI-2040.

Lorus also announced that GeneSense has received a patent issued by the Canadian Patent Office for GTI-2040.

Currently, development of GTI-2040 is being supported under a Clinical Trials Agreement with the United States National Cancer Institute (NCI). Given the potential for GTI-2040 to improve the efficacy of a number of chemotherapies, for a range of indications, clinical trials conducted under
the NCI-CTEP program involve combination therapy against non-small cell lung cancer, breast cancer, colorectal cancer, acute myeloid leukemia, prostate cancer and a variety of solid tumors.

Promising phase II interim clinical data arising from GTI-2040 in combination therapy for the treatment of renal cell carcinoma has provided evidence of disease stabilizations, tumor reductions and a favourable safety profile. Patients in this phase II clinical study had previously failed or
were ineligible for standard therapies, and were representative of a population with very poor prognostic outcome.

The Canadian patent and European patent allowance follows patents issued by the United States Patent Office and the Singapore, Australian and New Zealand Patent Offices. The patent application for this antisense drug has been filed in numerous additional international jurisdictions.

"These patents contribute to our strong global intellectual property portfolio, an important part of our strategy for creating shareholder value in our company," said Dr.Wright, CEO of Lorus Therapeutics.

GTI-2040 is an antisense drug that specifically targets the R2 component of ribonucleotide reductase,which is required for DNA synthesis and cell proliferation.

It has also been described as a malignant determinant that is elevated in a wide range of tumors,and through deregulation can cooperate with a variety of cellular cancer causing genes known as oncogenes to enhance tumor growth and metastatic potential.GTI-2040 showed significant antitumor activity against many different human tumors in preclinical studies.

In addition to the clinical trial in renal cell cancer described above, GTI-2040 is currently the subject of a Clinical Trials Agreement with the United States National Cancer Institute (NCI) under which GTI-2040 will be tested in combination chemotherapy in six different clinical trials. All of these trials have been initiated.

A SDF-1 Receptor Antagonist Shows Significant Reduction of Metastatic Lung Nodules Associated with Osteosarcoma

Sun, 20 Mar 2005 08:15:00 PST

( from http://www.rxpgnews.com ) Chemokine Therapeutics Corp., a biotechnology company developing drugs in the field of chemokines and cytokines, has announced that investigators at the National Cancer Institute (NCI) reported a two-thirds reduction in the number of visible metastatic lung nodules using the Company's investigational drug CTCE-9908 in a pre-clinical study of osteosarcoma.

The study results are consistent with a pre-clinical study of CTCE-9908 conducted by researchers at Chemokine Therapeutics. CTCE-9908 is designed to inhibit the growth and spread of certain common cancers with the potential for use with existing therapies (chemotherapy, surgery, and radiation) to improve treatment outcomes.

Osteosarcoma is a form of bone cancer which can spread (metastasize) to the lungs, bone marrow and liver.

The NCI findings will be the subject of a Poster Session on April 17th at the American Association for Cancer Research (AACR) 2005 Annual Meeting to be held in Anaheim, California. The abstract is available on Chemokine Therapeutics' website. The Company will announce additional information after the poster presentation at the American Association for Cancer Research Conference.

Recently, researchers discovered that the growth and spread of cancer are affected by a chemokine known as stromal cell-derived factor-1 (SDF-1). SDF-1 is produced naturally in organs such as the bone marrow, liver, and lungs and is an important regulator of stem cells.

SDF-1 acts on receptors which are expressed in both stem cells and various common cancers. The presence of these receptors on cancer cells allows the cancerous cells to migrate from the original cancer site to new sites that are rich in SDF-1, such as bone marrow, liver, and lungs, where they develop new blood vessels (angiogenesis) and form new tumors (metastases).

CTCE-9908 is an analog of SDF-1 and antagonist of SDF-1 receptors developed by scientists at Chemokine Therapeutics using rational-drug design.

CTCE-9908 binds competitively to the receptors on cancer cells which prevents the interaction of SDF-1 with the receptors. A recently completed Phase I study of this compound in healthy adults did not reveal any significant toxicity.

Chemokine has been collaborating with the National Cancer Institute's Pediatric Oncology Branch since February, 2004. The NCI continues to evaluate the oncological potential of CTCE-9908. The NCI is a component of the National Institutes of Health (NIH), one of eight agencies that compose the Public Health Service (PHS) in the Department of Health and Human Services (DHHS).

The NCI, established under the National Cancer Act of 1937, is the principal agency for cancer research and training of the United States federal government.

Helical Tomotherapy : Most Advanced form of Image-Guided Intensity Modulated Radiation Therapy

Tue, 15 Mar 2005 18:19:00 PST

( from http://www.rxpgnews.com ) M. D. Anderson Cancer Center Orlando is among the first centers in the world to possess and treat cancer patients with the TomoTherapy HI·ART ® system.

Considered to be the most advanced form of image-guided intensity modulated radiation therapy (IMRT), the system will be used to treat head, neck, prostate, lung and breast cancer.

Helical tomotherapy is the future of image-guided IMRT and is an important step forward in cancer treatment, said Dr. Patrick Kupelian, radiation oncologist and project leader for the tomotherapy project at M. D. Anderson - Orlando. Some patients currently ineligible for radiotherapy may be candidates for treatment because of tomotherapys enhanced precision.

Tomotherapy means slice therapy and gets its name from tomography, or cross-sectional imaging. The system is the first device to provide 3-D imaging immediately before treatment to verify the location of a patients tumor.

Tomotherapy delivers a very sophisticated form of IMRT while integrating treatment planning, patient positioning and treatment delivery in one system.

With this groundbreaking technology, treatments become more precise so that radiation can be altered to compensate for patient movement and the changing shape of the tumor being treated, explained Dr. Clarence H. Brown III, president/CEO of M.D. Anderson - Orlando. This translates into fewer side effects and may allow patients to complete their course of treatment in a shorter period of time.

Radiation therapy is typically delivered over many days, and a constant concern is daily changes that can affect the position of the target areas within the patient said Kupelian.

For example, special concerns for lung cancer patients include moving the slightest amount while breathing, even a couple of centimeters, as well as lung tumors that can progress within days, may change the anatomy of the target areas. Also, bladder or rectum filling might affect the position of the prostate gland during treatment for prostate cancer. This raises concerns that radiation meant for a tumor might accidentally hit and harm normal tissues. In addition, the tumor areas might get undertreated due to misalignment.

However, because the physician can accurately visualize the target areas, position adjustments can be made just prior to treatment.

Before beginning treatment, 3-D images from a CT scan and special computer software enable physicians to verify the position of a tumor and adjust a patient's position if necessary to make sure the radiation is directed to the correct location.

In addition, tomotherapy has the unique ability to record the dose and location of the radiation given to a patient, so physicians know what took place in the previous session, and can make adjustments if necessary elaborated Kupelian. Currently, that kind of information isnt available in any form of radiotherapy.

TomoTherapy, Inc., a University of Wisconsin (UW) technology transfer company, created helical tomotherapy. In addition to M. D. Anderson Orlando and UW, helical tomotherapy is slated for use in a limited research capacity at Cross Cancer Institute at the University of Alberta in Alberta, Canada, and at London Regional Cancer Center in Ontario, Canada.

Tomotherapy will be available at two other facilities in the U.S., including Thompson Cancer Survival Center in Knoxville, Tennessee, and Rapid City Regional Hospital, Rapid City, South Dakota.

Electronic Brachytherapy : The Next Generation Radiotherapy

Sun, 13 Mar 2005 08:41:00 PST

( from http://www.rxpgnews.com ) The delivery of localized radiation treatment directly to cancer sites using high dose rate x- rays on demand has significant potential to improve cancer treatment, according to a recent symposium on Electronic Brachytherapy at the 15th Annual Meeting of the American College of Radiation Oncology (ACRO).

Attended by approximately 75 leading radiation oncologists participating in the ACRO meeting, the symposium, titled "Electronic Brachytherapy: Early Experience and Future Potential" was led by Vivek Mehta, MD, Director for the Center of Advanced Targeted Radiation Therapy at Swedish Cancer Center in Seattle.

"Electronic Brachytherapy was designed to leverage all of the clinical benefits of traditional brachytherapy and external beam radiation without the radioactivity, without the concerns associated with handling isotopes and without the need for a shielded bunker," said Dr. Mehta.

The symposium was sponsored by Xoft, Inc., developer of the Axxent(TM) Electronic Brachytherapy System, a proprietary platform designed to deliver non-radioactive, isotope-free radiation treatment in virtually any clinical setting under radiation oncology supervision. The symposium reviewed the results of existing clinical trials in accelerated partial breast irradiation, the potential first use for electronic brachytherapy. In addition, Dr. Mehta presented results of work done in a pre-clinical setting that have demonstrated system performance, as well as previewed future indications and development plans.

"As electronic brachytherapy moves closer to clinical practice, all indications are that this technology represents a leap forward in cancer treatment," added Dr. Mehta. "And, as important as the clinical benefits are, the true breakthrough may relate to easy and convenient access to partial breast radiotherapy for the tens of thousands of women who today opt for an unnecessary mastectomy or a lumpectomy without radiation therapy."

The Electronic Brachytherapy System, which is not currently FDA cleared, uses disposable micro-miniature x-ray radiation sources to deliver treatment. Designed to deliver electronically generated ionizing radiation directly to tumor beds, this localized approach minimizes exposure of the patient's healthy tissue to toxic radiation.

A unique advantage is that it also minimizes radiation exposure to treatment staff. With Xoft's electronic brachytherapy technology, users can control energy level and total dose, allowing more flexibility than isotope-based systems -- but in a non-shielded or lightly shielded clinical environment.

In its first indication for use, the Electronic Brachytherapy System provides both the patient and the radiation oncologist the opportunity to reduce the time required for radiation therapy for early stage breast cancer from seven weeks (for external beam radiation therapy) down to five days.

As a result, tens of thousands patients will have greater access to therapy that is delivered more easily and conveniently. This may accelerate the choice of breast-sparing lumpectomy surgery instead of a full mastectomy (which does not require a long course of radiation).

Temozolomide Brings New Hope for Glioblastoma Patients

Thu, 10 Mar 2005 07:40:00 PST

( from http://www.rxpgnews.com ) A large international study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in collaboration with the National Cancer Institute of Canada (NCIC) Clinical Trials Group demonstrated that the addition of a novel chemotherapy agent, Temozolomide (brand name: Temodal(R)) to radiation therapy increases survival in patients suffering from glioblastoma, a very aggressive form of a brain tumour.

Further, molecular analyses of the tumour allowed for the identification of those patients most likely to benefit from this type of treatment. The findings are leading to a new standard of care for patients with this fast growing and devastating cancer. The results of this landmark trial are published in two companion papers in this weeks' edition of the New England Journal of Medicine (publication date: 10 March 2005).

Primary tumours originating in the brain account for less than 5% of all cancer diagnoses. However, brain cancer frequently affects previously healthy younger men and women in the middle of their most active life.

Glioblastoma is the most common type of primary malignant brain tumour in adults with a yearly incidence of 5-7 persons per 100.000. Thus in the European Union approx. 20'000 new patients are diagnosed every year. Glioblastoma is a rapidly growing malignant brain tumour and usually has a fatal outcome.

Prior to the discovery of this new therapy, the average life expectancy of patients with glioblastoma was about 1 year. The results of this study demonstrate a clear improvement of survival. At 2 years only 10% of patients treated with radiotherapy alone were alive, compared to 26% of patients receiving the combination of both radiotherapy and temozolomide chemotherapy.

If patients were to be selected according to their molecular profile -- the investigators analysed the functionality of a gene responsible for DNA repair, the so called MGMT gene -- the improvement is even more dramatic, as almost half of those patients whose tumours carry an inactivated MGMT gene are alive after 2 years.

Importantly, the study also showed that this new combined therapy did not impact negatively on the patients' quality of life. Health- related quality of life has become an increasingly important endpoint in cancer studies.

In this trial, almost 600 patients were randomised within less than one and a half years. This rapid accrual and final success would not have been possible without well-established structures for academic clinical research, like the EORTC and NCIC Clinical Trials Group.

Recently implemented new regulations in Europe with an increased administrative burden, complex liability and insurance issues as well as exploding costs have become a threat for future successful conduct of clinical trials.

This example illustrates that progress in cancer treatment requires well-functioning international collaborative networks and integrated laboratory-based science.

The EORTC also assembled a laboratory research team that succeeded in identifying a molecular change in the tumour that predicts benefit from this new therapy. Future brain tumour trials by the EORTC will continue to integrate clinical and basic research to further refine the molecular basis of brain cancer, find new therapeutic targets, and develop and test new treatments.

The lead investigators comment:

"This is the first trial to demonstrate that we can truly impact this devastating disease with chemotherapy. This is only a first step toward cure of brain cancer patients and should now fuel interest, continued international collaboration and research to further improve the outcome of these patients," says the lead author and trial initiator Roger Stupp, MD for the University Hospital Multidisciplinary Oncology Centre in Lausanne, Switzerland.

"Without the close collaboration between the hospital based research laboratory and the leading clinicians, this interdisciplinary success would never have been possible. I hope this example will stimulate a closer collaboration between basic and clinical research in the future," remarks Monika Hegi, PhD signing author for the translation research work and leader of the laboratory of Tumor Biology and Genetics of the University Hospital Lausanne Neurosurgery department and project leader at the National Center of Competence in Research (NCCR Molecular Oncology).

"In 25 years of academic cancer medicine, it is the first time that I have witnessed such a progress in any of the deadliest forms of human cancers. The study has also been an exceptional model of multidisciplinary as well as international cooperation, with such an outstanding input of so many participants," said co-investigator and radiation therapy protocol leader, Rene-Olivier Mirimanoff MD, at the Radiation Oncology Department of the University Hospital in Lausanne, Switzerland.

"Until now, there have been few treatment options for glioblastoma patients," says Dr. Gregory Cairncross, a pioneer in neuro-oncology research and one of the study's primary investigators and head of the Department of Clinical Neurosciences at the University of Calgary in Alberta, Canada. "The results of this trial will dramatically improve treatment and outcome for many of these patients and will open the door to further trials to expand this treatment combination. The key to the new therapy's effectiveness is that temozolomide causes very few side effects and is well tolerated by patients. This means patients can take the drug every day during their radiation treatment instead of once every eight weeks -- the common dosage for other chemotherapy drugs."

"This landmark study represents the most important advance in the management of glioblastoma since radiotherapy was shown to be of benefit over 35 years ago," comments Dr. Warren Mason, a lead investigators in Canada and head of the neuro-oncology unit at the Princess Margaret Hospital in Toronto, Ontario/Canada. "This study also identified MGMT the first clinically relevant molecular marker for glioblastoma which not only serves as a prognostic factor for survival, but also as a predictor for response to chemotherapy. This observation paves the way for using the unique tumor genetic signature as a guide for individualizing therapy and optimizing outcome."

A Novel RAF kinase and VEGFR Inhibitor as Single Agent Therapy for Advanced Hepatocellular Carcinoma - Under Trial

Wed, 09 Mar 2005 08:37:00 PST

( from http://www.rxpgnews.com ) Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.today announced the initiation of a randomized, double-blind, placebo-controlled Phase III clinical trial of BAY 43-9006 administered as a single agent in patients with advanced hepatocellular carcinoma (HCC), or liver cancer.

BAY 43-9006, a novel RAF kinase and VEGFR inhibitor under investigation for the treatment of different types of cancer, combines two anticancer activities: inhibition of tumor cell proliferation and angiogenesis (the growth of new blood vessels).

BAY 43-9006 is being evaluated in several clinical trials, including a Phase III randomized clinical trial for the treatment of renal cell carcinoma (RCC), or kidney cancer.

"BAY 43-9006 is the first raf kinase inhibitor to be tested in a worldwide HCC Phase III study," said Dr. Jordi Bruix, Head of the Barcelona Clinic Liver Cancer Group (BCLC), University of Barcelona, Spain. "Based on the results seen in the Phase II HCC studies, we are pleased to continue the clinical development of BAY 43-9006 in liver cancer, a difficult-to-treat patient population. HCC is a particularly aggressive type of cancer with a significant unmet treatment need. Because of this, it is vitally important to pursue research to develop potential new therapies for this disease." Dr. Bruix is co-primary investigator along with Dr. Josep Llovet, Senior Scientist, Division of Liver Disease, Mount Sinai School of Medicine, New York.

The Phase III study is designed to measure differences in overall survival, time to symptom progression and time to tumor progression of BAY 43- 9006 versus placebo in patients with advanced HCC. The trial will also evaluate the safety and pharmacokinetics of BAY 43-9006.

More than 500 patients with advanced HCC, who have not received previous systemic treatment for their disease, will be randomized to receive 400 mg of oral BAY 43-9006 twice daily or matching placebo. This study is expected to enroll patients in the Americas, Europe, and Australia/New Zealand.

"We are encouraged by the early Phase II findings in this patient population," said Susan Kelley, M.D., vice president, Oncology, Bayer Pharmaceuticals Corporation. "We look forward to the results of the Phase III trial as we continue to study this compound for patients who greatly need new treatments."

Results of the Phase II study in advanced HCC, completed last year, were reported in a scientific congress in September 2004. Of 137 patients enrolled in the study, investigators reported seven patients with partial responses (tumor shrinkage of 50 percent or greater), five with minor responses (tumor shrinkage of 25 to 50 percent) and 59 with stable disease for at least four months as their best response. Median overall survival for all patients was 9.2 months and median time-to-tumor progression (TTP) was 4.2 months.

In the study, safety data generated showed that BAY 43-9006 was well tolerated and side effects were predictable and manageable. The most common grade 3/4 drug-related toxicities were fatigue (9.5 percent), diarrhea(8 percent), and hand-foot skin reaction (5 percent).

Bayer and Onyx also reported today that the U.S. Food and Drug Administration (FDA) has completed a Special Protocol Assessment (SPA) for the Phase III HCC trial. An SPA is a written agreement on the design and size of clinical trials intended to form the basis for a new drug application.

The companies are also planning a Phase II trial for liver cancer patients to evaluate the use of BAY 43-9006 in combination with the chemotherapeutic agent doxorubicin.

BAY 43-9006, a novel investigational drug candidate, has demonstrated anti-proliferative and anti-angiogenic properties - two important anticancer activities. In preclinical models, BAY 43-9006 inhibited tumor cell proliferation by targeting the RAF/MEK/ERK signaling pathway at the level of RAF kinase.

BAY 43-9006 also exerted an antiangiogenic effect by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR and their associated signaling cascades. BAY 43-9006 also inhibits other tyrosine kinases such as c-KIT and FLT-3.

BAY 43-9006 has shown anticancer activity in a number of tumor types. It is being evaluated both as a single agent therapy and in combination with other oncology agents in a number of ongoing clinical trials.

Hepatocellular carcinoma, also known as primary liver cancer, is the most common form of liver cancer and is responsible for 80 percent of the primary malignant liver tumors in adults. It is the fifth most common cancer in the world. In 2002, approximately 626,000 HCC cases were reported worldwide, with 15,000 cases in the United States and 53,600 in Europe.

HCC is most prevalent in developing countries, particularly in East and South-east Asia, the Pacific Basin, and sub-Saharan Africa. Of the 626,000 cases worldwide, approximately 410,000 were reported in Eastern Asia (with 346,000 in China and 40,000 in Japan alone). HCC causes more than 600,000 deaths annually worldwide. The five-year relative survival rate is about seven percent.

A Novel Murine Monoclonal Antibody, 3G4 , Targets Phospholipids to Treat Cancer

Tue, 08 Mar 2005 14:43:00 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, Inc.announced today the publication of data in 'Clinical Cancer Research' demonstrating significant anti-tumor activity in various tumor models using the murine monoclonal antibody 3G4, an equivalent of the company's Tarvacin(TM), that recognizes anionic phospholipids exposed on the surface of tumor blood vessels. These studies were performed by researchers at University of Texas Southwestern Medical Center at Dallas.

The article stated that treatment with 3G4 as a monotherapy inhibited the growth of various different tumors in mice. It reduced the growth by up to 75% in established human breast tumor models, up to 90% in a mouse fibrosarcoma model, and 50% in a human Hodgkin's tumor model.

"Our results demonstrate the targeting of phospholipids as a means to treat cancer," stated Dr. Philip Thorpe, Professor of Pharmacology at the University of Texas Southwestern Medical Center at Dallas."The activity seen
in multiple solid tumor types in this study also confirms the Vascular Targeting approach as a broad spectrum treatment."

Peregrine has generated a chimeric 3G4 clinical candidate that it is developing under the trade name Tarvacin(TM). Peregrine recently received approval from the FDA for its murine monoclonal antibody Phase I study for the treatment of cancer. This murine monoclonal antibody, a novel anti-cancer agent, is part of Peregrine's Anti-Phospholipid Therapy platform, which binds directly to tumor blood vessels to inhibit tumor growth and development. The company plans on initiating patient enrollment in the approved Phase I study in the near term.

This murine monoclonal antibody is part of Peregrine's Anti-Phospholipid Therapy platform,which binds directly to tumor blood vessels to inhibit tumor growth and development. The said compound is a chimeric monoclonal antibody that binds to the phospholipid, phosphatidylserine. This murine monoclonal antibody was initially discovered by researchers at UT Southwestern, who have worked closely with Peregrine to explore the potential activity and safety of this murine monoclonal antibody as a treatment for cancer.

Peregrine has a sponsored research agreement with researchers at UT Southwestern to study the use of this murine monoclonal antibody and its parent antibody for the treatment of cancer and viral diseases. In addition, the researchers at UT Southwestern have also received grants to study the use of anti-phospholipid therapeutics for the treatment of viral infections and diseases. Peregrine is also collaborating with The Foundation Fighting Blindness to study APT constructs as well as Vascular Targeting Agents (VTAs) for the treatment of eye diseases.

Peregrine and its research collaborators have completed a number of pre-clinical animal experiments using this murine monoclonal antibody to study the safety and efficacy of the compound. In pre-clinical studies, the monoclonal antibody binds to tumor blood vessels and demonstrated significant anti-tumor activity in animal cancer models.

Enhanced tumor effects were observed when this murine monoclonal antibody was administered in conjunction with chemotherapy and radiation therapy. In addition, in data recently presented at the American Association of Cancer Research (AACR), 3G4, the parent antibody of Tarvacin(TM), was shown to reduce the growth of breast cancer tumors in animal models by 60% when given alone and by 93% when given in combination with the commonly used chemotherapy drug docetaxel.

These data, in combination with other data presented during the year, have heightened the company's excitement and commitment to this murine monoclonal antibody program.

A Vaccine For Carcinoma Cervix

Fri, 04 Mar 2005 10:06:00 PST

( from http://www.rxpgnews.com ) A vaccine to prevent a type of cancer that kills more than 250,000 women around the globe every year is expected to become available within a year or two, thanks in large part to technology developed by scientists at the University of Rochester Medical Center.

Vaccines that prevent cervical cancer are in the final stages of testing in studies by two companies, Merck and Co. and GlaxoSmithKline (GSK). Earlier this month the two pharmaceutical giants agreed on a settlement involving patents and royalties related to the vaccines, clearing the way for continued development of their products.

The vaccine targets a group of viruses known as human papillomaviruses (HPV), which cause 12,000 cases of cervical cancer in women in the United States annually. About 4,500 women in the nation die of the disease every year. The toll is much worse in other parts of the world, where Pap smears to detect the disease in its earliest stages are not widely available. In some parts of the world, cervical cancer is the leading cause of death by cancer in women.

Research done more than a decade ago by a trio of University virologists Richard Reichman, M.D., William Bonnez, M.D., and Robert Rose, Ph.D. is integral to the technology, which takes aim at a portion of a class of viruses that also cause all warts.

A patent application was filed, and the rights to the technology were licensed to the biotechnology company MedImmune, which then sold the license to SmithKline (which later became GSK). Now, the research is poised to save lives and become part of one of the first vaccines to prevent a form of cancer. (The hepatitis B vaccine can also prevent liver cancer.)

The public health impact of this work which has the potential to prevent a condition that causes significant morbidity and mortality in women is enormous, both nationally and internationally, says David Guzick, M.D., Ph.D., dean of the School of Medicine and Dentistry and professor of Obstetrics and Gynecology.

Pretty much everyone has encountered an HPV in one form or another. There are more than 100 types of HPV. Some cause common warts on the hands or plantar warts on the feet. At least 40 types of HPV infect the genital tract, causing warts in some people and a variety of other conditions, most notably cervical cancer and other cancers in women, anal cancer in men and women, and occasionally penile cancer in men.

In the United States, more than 15,000 people every day, or about 5.5 million people a year, get sexually transmitted HPV infections from their partners. About three out of every four sexually active people will get an HPV infection at some point during their lifetime; in some age groups, such as sexually active men and women under the age of 30, doctors estimate that 40 percent of people are currently infected.

Most people fight off the virus and never even know they were infected. Others have warts. In the most serious cases, in about 1 percent of women with the virus, it progresses to abnormal cell growth known as dysplasia and sometimes to cervical cancer. Two types of HPV, type 16 and type 18, cause about 70 percent of cervical cancers, and those are the types that the two current vaccines in development are designed to prevent.

Scientists have published results in the Lancet and New England Journal of Medicine that show that both vaccines protect against those two types of HPV, and now both vaccines are being studied in larger studies involving tens of thousands of women. The vaccines are given as a series of three shots given a few months apart.

Scientists and public health officials are discussing who should receive the vaccine, and when; most doctors say the vaccine would need to be given before a person becomes sexually active to do the most good. Women have the most to gain from protection against HPV, while men who were protected may be much less likely to spread the disease.

The key to the technology is VLPs, or virus-like particles, which have become VIPs in the world of infectious disease. Twenty years ago the team set out on a basic research study to look at how a persons immune system fights HPV infection. The team soon focused on the actual viral particle that causes the disease.

After discovering that the body produces antibodies that could neutralize the virus, they figured out how to make harmless virus-like particles to trigger the same immune response. They did this by putting an HPV gene into insect cells using a virus called baculovirus, which infects insects; the HPV gene then produces particles that mimic the shape of real HPV particles.

Each member found his way to Rochester and the field of HPV for his own reasons. Reichman, director of the Infectious Diseases Unit, was an expert on sexually transmitted viral diseases and took the advice of a visiting senior colleague that human papillomaviruses offered a good research opportunity.

Bonnez, a classically trained virologist, came to the United States from France largely for the opportunity to do research on viruses while still treating patients. And as a graduate student, Rose sought an opportunity to study viruses and their structure in a way that would have an impact on human health.

The medical center was able to bring together individuals from disparate backgrounds who have this common link, an interest in science as a vehicle to improve the health of populations. This extraordinary achievement, in which basic science discoveries are translated into clinical and public health practice, is the essence of what an academic medical center is all about, says Guzick.

With VLPs in hand, the team promptly filed for a patent and in early 1997 began one of the worlds first tests in humans of a vaccine to prevent HPV infection. That study of 65 people found that the vaccine was safe and provokes an immune response in people and prompted further studies, culminating in a promising product for GSK. Like any vaccine, the products are designed to trigger an immune response, so that if the person encounters the disease, the body is primed to fight it off.

Marjorie Hunter, director of the medical centers Office of Technology Transfer, led recent negotiations that have helped iron out the intellectual property agreements. A previous technology transfer director, Robert Goodwin, helped link the researchers with MedImmune in 1995, a key step in keeping the technology alive. Also important was the consistent support and dogged determination of Michael Goldman of the Rochester law firm Nixon Peabody, who filed the initial patent.

Reichman, Rose and Bonnez continue to do research on HPV and other diseases. Reichman is investigating cervical HPV disease in women infected with HIV; Rose focuses on development of needle-free methods for delivery of the vaccine in developing countries; and Bonnez pursues his interests in defining exactly how the virus causes disease. In addition, Rose and Bonnez are members of a large team of investigators led by Tim Mosmann, Ph.D., director of the Center for Vaccine Biology and Immunology, who are looking at how and why the immune system naturally fights off HPV in some people but not in others.

Mapatumumab :TRAIL receptor 1 Agonistic Human Monoclonal Antibody for Advanced Non-Hodgkin's Lymphoma Reaches Phase 2 Trial

Fri, 04 Mar 2005 09:37:00 PST

( from http://www.rxpgnews.com ) Human Genome Sciences, Inc.announced today that it has completed the enrollment and initial dosing of patients in a Phase 2 clinical trial of HGS-ETR1 (mapatumumab) in advanced non-Hodgkin's lymphoma.

The Phase 2 clinical trial is a multi-center, open-label study to evaluate the efficacy, safety and tolerability of HGS-ETR1, an agonistic human monoclonal antibody to TRAIL receptor 1, in patients with relapsed or refractory non-Hodgkin's lymphoma.

Patients enrolled in the trial are receiving up to six cycles of treatment in the absence of disease progression, with HGS-ETR1 administered as an intravenous infusion once every twenty-one days.

The objectives of the study are to evaluate disease activity and tumor response to HGS-ETR1 in patients with advanced non-Hodgkin's lymphoma, to evaluate the safety and tolerability of HGS-ETR1, and to determine plasma concentrations of HGS-ETR1 for use in a population pharmacokinetic analysis.

On November 30, 2004, Human Genome Sciences announced the completion of enrollment and initial dosing of patients in a Phase 2 study of HGS-ETR1 in advanced non-small cell lung cancer.On February 23, 2005, the company announced the completion of enrollment and initial dosing of a Phase 2 study of the drug in advanced colorectal cancer.

The three Phase 2 studies of HGS-ETR1 initiated to date fit into a global clinical development program through which Human Genome Sciences is evaluating the novel, genomics-derived anticancer drug's potential for use in the treatment of specific cancers.

Anas Younes, M.D., Professor, Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, said, "The current standard of care for non- Hodgkin's lymphoma calls for treating most patients with a combination of chemotherapy and, in recent years, monoclonal antibodies. This therapeutic approach produces cures in approximately fifty percent of patients with aggressive lymphoma. Additional chemotherapeutic and other therapeutic modalities are used to treat non-Hodgkin's lymphoma patients who relapse or do not respond, but cures are difficult to achieve. There remains a significant need for new therapies that can improve response rates, extend the duration of response, extend survival, minimize toxicity, and provide patients with improved quality of life. We look forward to continuing the evaluation of HGS-ETR1 to determine whether it may play a role in the treatment of non- Hodgkin's lymphoma."

Gilles Gallant, B. Pharm., Ph.D., Vice President, Clinical Oncology, said, "We are pleased to have completed the enrollment and initial dosing of three Phase 2 studies to evaluate the potential use of HGS-ETR1 as a treatment for specific cancers, including non-small cell lung cancer, colorectal cancer and, now, non-Hodgkin's lymphoma. We have seen a high level of interest in the emerging clinical and preclinical evidence demonstrating that agonistic antibodies to TRAIL receptors 1 and 2 have significant potential to provide novel therapeutic options to patients with a variety of cancer types, including non-Hodgkin's lymphoma.We expect to have the results of all three of the ongoing Phase 2 studies of HGS-ETR1 available in 2005. We also have initiated Phase 1b clinical studies of HGS-ETR1 in combination with chemotherapy. We plan to continue to elucidate the potential of HGS-ETR1 as a treatment for non-Hodgkin's lymphoma and solid tumor malignancies, both as a single agent and in combination with chemotherapeutic agents."

Interim results of two ongoing Phase 1 multi-center, open-label, dose- escalation clinical trials of HGS-ETR1 were presented in September 2004 at the 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland.The data presented demonstrate the safety and tolerability of HGS-ETR1 in patients with advanced solid tumors or non- Hodgkin's lymphoma, and support further evaluation of HGS-ETR1 in Phase 2 clinical trials, both as a single agent and in combination with chemotherapy.

Data were presented on 39 patients treated to date in a Phase 1 study conducted in patients with advanced solid tumors. Interim results of the ongoing study demonstrate that HGS-ETR1 can be administered safely and repetitively to patients with advanced solid malignancies at doses up to and including 10 mg/kg intravenously every 28 days. Some preliminary evidence of biological activity has been observed. Durable stable disease was observed in some patients.

Data also were presented on 24 patients treated to date in an additional Phase 1 study conducted in patients with advanced solid tumors or non-Hodgkin's lymphoma. Results presented from the ongoing clinical trial demonstrate that HGS-ETR1 is well tolerated with no clearly attributable toxicities to date and that the Maximum Tolerated Dose has not been reached. Stable disease has been observed in eight patients for greater than two cycles. The trial continues to enroll patients.

Human Genome Sciences, using genomic techniques, originally identified the TRAIL receptor-1 protein as a member of the tumor necrosis factor receptor super-family. The company's own studies, as well as those conducted by others, show that TRAIL receptor 1 plays a key role in triggering apoptosis, or programmed cell death, in tumors.

Human Genome Sciences took the approach of developing human monoclonal antibodies that would bind the receptor and stimulate the TRAIL receptor-1 protein to trigger apoptosis in cancer cells, in much the same way that the native TRAIL ligand (tumor necrosis factor- related apoptosis-inducing ligand) triggers it, but with the advantage of a longer half-life and an exclusive specificity for TRAIL receptor 1.

The TRAIL receptor 1 agonistic human monoclonal antibody, HGS-ETR1, was made in a collaboration between Human Genome Sciences and Cambridge Antibody Technology. The drug will be produced in the Human Genome Sciences clinical manufacturing facilities located in Rockville, Maryland. Human Genome Sciences holds the commercial rights to the drug.

Non-Hodgkin's lymphoma is the seventh most common cancer in the United States, with approximately 56,000 new cases diagnosed each year.

Electrochemical Ablation Technique Brings New Hope For Locally Advanced Pancreatic Carcinoma

Thu, 03 Mar 2005 17:12:00 PST

( from http://www.rxpgnews.com ) Genetronics Biomedical Corporation , a late stage developer of oncology and other therapies using electroporation to deliver drugs and nucleic acids, announced today that it has initiated a Phase I clinical trial to treat pancreatic cancer using its MedPulser® Tumor Ablation System. The FDA has granted Genetronics orphan designation for this indication.

The primary endpoint of this FDA-approved study is to determine the safety profile of the MedPulser® electroporation therapy in conjunction with intralesionally-injected bleomycin for the treatment of unresectable or incurable locally advanced pancreatic cancer.

The secondary endpoints are to assess objective tumor response, patient pain, and weight loss over 24 weeks following electroporation therapy. Genetronics aims to complete enrollment of up to 12 patients by the end of 2005.

"There is typically tremendous pain associated with pancreatic cancer and a lack of good treatment options to control this pain, leading to very poor quality of life in the final stages of the disease. We believe the Medpulser® Tumor Ablation System may provide an important new approach to alleviate and control this pain and enhance patients' quality of life," stated Avtar Dhillon , President and CEO of Genetronics. "This study will also exhibit the ability of our electrochemical ablation technique to treat solid tumors inside the body cavity, which may significantly expand the number of solid tumor applications and greatly enhance the market potential of the MedPulser system."

The Office of Orphan Product Developments has granted Genetronics orphan designation for the treatment of pancreatic cancer. Upon successfully securing marketing approval from the FDA for this indication, Genetronics could then also secure orphan drug status, providing U.S. marketing exclusivity for seven years and certain tax benefits.

Genetronics' electroporation therapy using bleomycin has been shown to have anti-tumor activity against resistant human pancreatic adenocarcinoma cells in previous in vitro and in vivo studies.

Over the past half-century, the incidence of pancreatic carcinoma has increased dramatically in the U.S., Europe, and Japan . In 2004, an estimated 31,860 new cases of pancreas cancer were expected to be diagnosed in the U.S. and an estimated 31,270 deaths were expected to occur. The five-year relative survival rate is about 4% for all disease stages combined, with a five-year survival rate of only 17% survival for local disease.

Surgical resection (removal of all or part of an organ, tissue, or structure) is the only option to cure a local pancreatic malignancy. However, only 10% to 20% of patients with pancreatic cancer are candidates for surgical resection.

Current standard therapy of advanced disease where resection is not viable involves the use of chemotherapy to provide some clinical benefit from pain, loss of performance, or weight loss.

However, pain is still the most disturbing symptom of pancreatic cancer, affecting 30% to 40% of the patients by the time of death.

A Technologically Advanced Tool for Difficult-to-Treat Cancers

Mon, 28 Feb 2005 21:08:00 PST

( from http://www.rxpgnews.com ) Cancer recently surpassed heart disease as the top killer of Americans under 85, according to the American Cancer Society. Lung cancer, as well as cancers along the spine, have always been the most difficult sites to treat due to respiratory motion and the proximity of critical organs. With FDA 510(k) clearance of the Elekta Beam Modulator(TM), clinicians can offer patients new hope through more accurate treatments that spare more of the surrounding healthy tissue.

The Elekta Beam Modulator(TM) is a precision multi-leaf collimator designed for use with Elekta's medical linear accelerators. It shapes the radiation beam to more closely conform to the exact shape of the tumor, thereby allowing greater accuracy and smaller treatment fields. This makes Elekta technology ideal for targeting typically difficult-to-treat cancers of the lung and spine, as well as other sites in the body.

This advance in treatment precision demonstrates Elekta's superior technology and commitment to developing treatment enhancements that improve the efficacy and outcomes of cancer treatment. "Elekta's solutions give clinicians the most technologically advanced tools available to aggressively battle cancer," said Anthony De Carolis, President and CEO of Elekta, Inc. "Elekta remains at the forefront of technology, business solutions and treatment solutions. Our commitment to R&D and expanding our solutions will continue to fuel Elekta's growth, as well as the growth of centers using our technologies."

Temple University Health System, in Philadelphia, PA, is building a radiation oncology department from the ground up in the $77 million Ambulatory Care Center currently under construction. "To equip this facility we wanted to acquire the most cutting-edge technology available. We looked exhaustively at existing options and decided that Elekta offers that technology," stated Curtis Miyamoto, M.D., Department Chair of Radiation Oncology, Temple University Health System (Philadelphia, PA, USA).

Elekta was the first manufacturer to start research on image-guided radiation therapy (IGRT) in the mid-1990s, the first to have IGRT systems in clinical use, and the first to bring these solutions to market with Elekta Synergy(R). Elekta Synergy(R) systems, and now the Elekta Beam Modulator(TM), remain the most advanced weapons in the fight against cancer, with an imaging system integrated into the radiation treatment platform.

This technology enables physicians to obtain images of patients at the point of treatment, allowing them to visualize tumors at the time of treatment and to precisely target tumors while minimizing damage to surrounding tissue.

With Elekta Beam Modulator(TM), clinicians can obtain fine resolution beam shaping for challenging indications throughout the body, where treatment objectives typically include decreasing the number of treatment sessions, limiting the volume of normal tissue exposed to radiation, and increasing dose.

Pegfilgrastim Significantly Reduces the Incidence of Febrile Neutropenia in Patients on Chemotherapy

Sun, 27 Feb 2005 13:43:00 PST

( from http://www.rxpgnews.com ) Amgen Inc., the world's largest biotechnology company, today announced that data from the largest randomized placebo-controlled study to date for Neulasta(R) (pegfilgrastim) has been published in the February 20 issue of The Journal of Clinical Oncology.

The phase 3 study showed that administering pegfilgrastim beginning in the first and subsequent cycles of chemotherapy reduced the incidence of febrile neutropenia (low white blood cell count with fever), a serious complication of cancer chemotherapy typically associated with infection, by more than 90 percent.

"In this study, pegfilgrastim administered 24 hours after chemotherapy profoundly reduced the rate of febrile neutropenia from 17 percent to one percent," said the study's lead investigator Charles Vogel, M.D., Cancer Research Network, Plantation, Fla. "The high frequency of first-cycle febrile neutropenia in this study emphasizes the need to initiate pegfilgrastim from the first cycle of chemotherapy to significantly reduce the patient's risk of infection."

Febrile (or feverish) neutropenia is the most common presentation of infection in patients receiving chemotherapy. Infection in this setting can be serious and even life threatening because chemotherapy can compromise the patient's ability to fight infection.

Data from the randomized, double-blind, placebo-controlled study of 928 breast cancer patients show that first and subsequent-cycle administration of pegfilgrastim resulted in a 94 percent reduction in the incidence of febrile neutropenia, a 93 percent reduction in the incidence of hospitalization and an 80 percent reduction in the incidence of intravenous anti-infective use in patients receiving myelosuppressive chemotherapy previously considered at moderate risk for neutropenic complications.

Specifically, in all cycles, one percent of patients in the pegfilgrastim arm (6/463) developed febrile neutropenia compared with 17 percent of patients in the placebo arm (78/465). Pegfilgrastim was also associated with a significantly lower incidence of hospitalizations with one percent of patients (6/463) requiring hospitalization versus 14 percent of patients receiving placebo (64/465).

Two percent of patients in the pegfilgrastim arm (7/463) required intravenous anti-infectives versus 10 percent of patients in the placebo arm (48/465). Febrile neutropenia occurred most often in placebo patients during the first cycle of chemotherapy (65 percent). There were two deaths from septic shock on the placebo arm compared to zero in the pegfilgrastim arm.

In addition, first-cycle administration of pegfilgrastim resulted in a 91 percent reduction in the incidence of febrile neutropenia occurring in the first cycle of chemotherapy, an 89 percent reduction in the incidence of hospitalization and an 83 percent reduction in the incidence of intravenous anti-infective use.

Breast cancer patients (Stage 1-4, ECOG performance of 0-2) receiving 100 mg/m(2) docetaxel every three weeks for up to four cycles were randomized to receive either 6 mg pegfilgrastim (n=463) or placebo (n=465) once-per-cycle on the day after docetaxel administration for up to four cycles.

Docetaxel is associated with an average reported febrile neutropenia incidence of approximately 10 to 20 percent in the absence of growth factor support. Febrile neutropenia was defined as fever with a temperature greater than or equal to 38.2 degrees C and an absolute neutrophil count (ANC) less than 0.5 x 10(9)/L measured the same day or the day after fever was documented.

Pegfilgrastim was well-tolerated in this study with an adverse event profile similar to placebo. Bone pain was a frequently observed adverse event in both arms of the study (31 percent with pegfilgrastim versus 27 percent with placebo).

Pegfilgrastim was approved by the U.S. Food and Drug Administration (FDA) in 2002 for decreasing the incidence of infection, as manifested by neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Similar indications for pegfilgrastim were approved in Europe and Australia the same year.

Rare cases of splenic rupture and sickle cell crises have been reported in postmarketing experience. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure.

However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment. In clinical trials, the only serious adverse event not attributed to the underlying disease or chemotherapy was a case of hypoxia.

The most common adverse event attributed to pegfilgrastim was bone pain, reported in 26 percent of patients. While not reported in patients receiving pegfilgrastim, rare events of adult respiratory distress syndrome have been reported in patients receiving the parent compound, Filgrastim.

How Tumor Cells Acquire Resistance to Kinase Inhibitors

Tue, 22 Feb 2005 21:32:00 PST

( from http://www.rxpgnews.com ) Acquired resistance to chemotherapy is a major obstacle to successful cancer treatment. Understanding the mechanisms by which tumors become resistant to a particular agent is key to identifying new drugs or combination regimens.

Kinases are signaling molecules that control many aspects of cell behavior, including cell proliferation, i.e., whether and how fast cells divide. Abnormally active kinases promoting tumor growth are found in many cancers and are a focus of rational cancer drug design. One target for kinase inhibitors is the epidermal growth factor receptor (EGFR). Two EGFR inhibitors, gefitinib and erlotinib, showed therapeutic benefits in a subset of patients with non-small cell lung cancer. Recent work has helped us understand why some patients respond and some dont: responsive tumors usually harbor activating mutations in the EGFR gene, which somehow make the tumors sensitive to treatment. Nearly all patients whose tumors initially respond to EGFR inhibitors, however, eventually become resistant to the drugs and progress despite continued therapy.

William Pao and colleagues examined tumors from six patients with non-small cell lung cancer who initially responded to gefitinib or erlotinib but subsequently relapsed. Tumors from all six patients carried activating mutations in the EGFR gene. In addition, in three out of the six cases, the resistant tumor cells carried an identical second mutation in the EGFR gene. Whereas the activating mutation was present in tumor cells before treatment with erlotinib or gefitinib, the second mutation was not found in pre-treatment biopsies from these patients, nor in over 150 lung cancer samples from patients who had not been treated with either drug. Additional cell culture studies supported the notion that the secondary mutation causes resistance to gefitinib or erlotinib. It is clear, though, that this is only one mechanism of resistance, because in the three other cases resistance occurred in the absence of the second mutation. What caused the resistance in those tumors is not known.

All kinases share some common features, and a resistance mutation very similar to the one identified here has also been found in other kinase genes from tumors with acquired resistance to imatinib, another kinase inhibitor. As Gary Gilliland and colleagues point out in an accompanying Perspective (DOI: 10.1371/journal.pmed.0020075), the initial identification three years ago of resistance mutations against imatinib led to the rapid development of alternative kinase inhibitors that work even against tumors with the resistance mutation. Similarly, the results by Pao and colleagues should help researchers develop second generation drugs for lung cancer.

Epstein Barr virus may provide an ideal target for anti-cancer therapy

Thu, 17 Feb 2005 21:33:00 PST

( from http://www.rxpgnews.com ) A typically innocuous virus found in 90 percent of people worldwide is the key to a new treatment for a cancer particularly common in North Africa and Southeast Asia. A new study showing that antigens produced by the Epstein Barr virus may provide an ideal target for therapy will be published in the March 1, 2005, issue of Blood, the official journal of the American Society of Hematology.

Ten patients diagnosed with advanced nasopharyngeal carcinoma took part in the study these patients also tested positive for the Epstein Barr virus, a member of the herpes family responsible for the "kissing disease" (mononucleosis) and commonly associated with this cancer's tumors.

Patients were given intravenous doses of specialized T cells that specifically targeted antigens produced by the Epstein Barr virus. Developed by researchers from the Center for Cell and Gene Therapy at Baylor College of Medicine, Methodist Hospital in Houston, and Texas Children's Hospital, these T cells were created using the patient's own blood to recognize the antigens and destroy the cancerous cells harboring the virus. The treatment was well tolerated in all but one patient, who had pre-existing facial swelling that increased after the infusion.

"Radiation and chemotherapy, the traditional treatments for nasopharyngeal carcinoma, frequently fail and can cause severe long-term side effects," said senior study author Helen Heslop, M.D., Professor of Medicine and Pediatrics at Baylor College of Medicine. "There is a compelling need for therapies that can improve disease-free survival without severe toxicity. This study demonstrates that virus-specific T cells show remarkable activity in some patients with this cancer and this may lead to new treatments for nasopharyngeal carcinoma."

A majority of the patients (six) remain completely disease-free one to two years after the treatment. Two patients had no response to the treatment. One patient's cancer progressed after the infusion, which required the addition of chemotherapy. However, the patient experienced a partial remission, whereas previous chemotherapy treatments alone had had no effect. The tenth patient's disease did not better or worsen, but remained stable after treatment.

"This very important work combines the use of a novel target the antigen produced by the Epstein Barr virus with the use of cells directed at that protein," notes Donald M. Miller, M.D., Ph.D., Director of the James Graham Brown Cancer Center in Louisville, Kentucky. "The authors provide considerable hope that this approach will realize the important potential of cell-based therapies."

How green tea extract works to counteract the development of cancer

Wed, 16 Feb 2005 15:54:00 PST

( from http://www.rxpgnews.com ) A study on bladder cancer cells lines showed that green tea extract has potential as an anti-cancer agent, proving for the first time that it is able to target cancer cells while leaving healthy cells alone.

The study, published in the Feb. 15, 2005 issue of the peer-reviewed journal Clinical Cancer Research, also uncovered more about how green tea extract works to counteract the development of cancer, said JianYu Rao, a Jonsson Cancer Center member, an associate professor of pathology and laboratory medicine and the study's senior author.

"Our study adds a new dimension in understanding the mechanisms of green tea extract," Rao said. "If we knew exactly how it works to inhibit the development of cancer, we could figure out more precisely which bladder cancer patients might benefit from taking it."

Numerous epidemiologic and animal studies have suggested that green tea extract provides strong anti-cancer effects in several human cancers, including bladder cancer. It has been shown to induce death in cancer cells, as well as inhibiting the development of an independent blood supply that cancers develop so they can grow and spread.

In the UCLA study, which brought together researchers from UCLA's Jonsson Cancer Center, School of Public Health, Center for Human Nutrition and the departments of Pathology and Laboratory Medicine, Surgery, Urology and Epidemiology, scientists were able to show that green tea extract interrupts a process that is crucial in allowing bladder cancer to become invasive and spread to other areas of the body.

Green tea extract affects actin remodeling, an event associated with cell movement. When a human moves, the muscles and skeletal structure operate together to facilitate that movement. For cancer to grow and spread, the malignant cells must be able to move. The cell movement depends on actin remodeling, which is carefully regulated by complex signaling pathways, including the Rho pathway. When actin remodeling is activated, the cancer cells can move and invade other healthy cells and eventually other organs. By inducing Rho signaling, the green tea extract made the cancer cells more mature and made them bind together more closely - a process called cell adhesion. Both the maturity of the cells and the adhesion inhibited the mobility of the cancer cells, Rao said.

"In effect, the green tea extract may keep the cancer cells confined and localized, where they are easier to treat and the prognosis is better," Rao said. "Cancer cells are invasive and green tea extract interrupts the invasive process of the cancer."

Bladder cancer is the fifth most common cancer in the United States, with about 56,000 new cases diagnosed each year. About half of all bladder cancers are believed to be related to cigarette smoking. Without a reliable, non-invasive way to diagnose the disease, bladder cancer can be difficult to detect in the early, most treatable stages. When not found early, the tumors can be aggressive, and more than half of patients with advanced cancers experience recurrences.

UCLA researchers currently are seeking hundreds of former smokers who have had bladder cancer for a clinical trial studying whether green tea extract prevents recurrence - one of the first studies in the country to test the agent on cancer patients. The study is part of a comprehensive program funded by the National Cancer Institute and designed to prevent the recurrence and progression of smoking-related bladder cancer. In addition to the trial, the program seeks to develop new biomarker tests to help predict who will get bladder cancer, discover the molecular profile of the disease to identify those most at risk and create a tumor bank to aid research. Volunteers interested in participating in the study should call (310) 825-4415.

Rao cautioned that his study was conducted in a carefully controlled cell line environment and that more research needs to be done to discover exactly how green tea extract functions as a cancer fighter. The next phase of his research will analyze urine from bladder cancer patients to determine which subset of patients would benefit most from taking green tea extract. Researchers will be looking for specific biomarkers associated with actin remodeling and activation of the Rho signaling pathway.

"We're hoping the results from these studies will tell us who will best benefit from the agent," Rao said, adding that the basic research he is doing and the clinical trial on bladder cancer patients will provide scientists with vital information from both ends the research continuum, an example of bench-to-bedside-and-back-again science.

"I think this publication further supports the potential role of green tea in the prevention and treatment of bladder cancer," said Dr. Robert Figlin, a UCLA professor of hematology/oncology and urology and a principal investigator for the human studies. "In the end, both studies will help us achieve our goal - to decrease bladder cancer occurrence and develop molecular profiles that tell us who is most at risk."

New insight into how tumor cells can become resistant to anti-cancer therapy

Tue, 18 Jan 2005 12:46:00 PST

( from http://www.rxpgnews.com ) A new study by researchers at Memorial Sloan-Kettering Cancer Center and The Johns Hopkins University provides new insight into how tumor cells can become resistant to anti-cancer therapy.

The scientists observed that a protein called P-glycoprotein (P-gp), which causes resistance to chemotherapy in many tumor types, is able to physically "jump" or transfer between tumor cells and retain its functional properties, protecting otherwise sensitive cells from the effects of anti-cancer treatment in vivo and in vitro. According to the authors, the research is the first to demonstrate that a protein transferred between cells retains its function long enough to allow the recipient cells to survive potentially toxic drug concentrations and ultimately develop intrinsic resistance.

In other words, cells that would normally be sensitive to treatment can develop resistance to it by receiving P-glycoprotein from other cells, making chemotherapy much less efficient. Uncovering the mechanism of this unusual "jumping" of the protein between the cells can potentially improve treatment success.

The authors conclude that their findings offer a new way in which to look at how cells behave in a community of cells within a tumor mass. The results have important implications for genomic analyses within tumor samples because resistance to cancer therapy can be achieved by protein transfer alone.

Timing appears essential to combining antiangiogenesis and radiation therapy

Tue, 21 Dec 2004 17:13:00 PST

( from http://www.rxpgnews.com ) Although the earliest clinical trials of the cancer-fighting potential of antiangiogenesis drugs did not have the dramatic results that some hoped for, subsequent trials showed that combining agents that suppress blood-vessel growth with therapies that destroy cancer cells can improve patient survival. In the December issue of Cancer Cell, researchers from the Massachusetts General Hospital (MGH) describe how timing may be crucial to successfully combining angiogenesis inhibitors with radiation treatment and reveal more about exactly how these drugs work to fight cancer, which is somewhat different from earlier theories.

"The blood vessels that develop to supply nutrients to a tumor are not normal," says Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Therapy, the study's senior author. "The vessels are leaky, dilated, disfigured, and do not evenly inflitrate the tumor, which can interfere with standard cancer therapies. Chemotherapy drugs are not distributed throughout the tumor, and the oxygen level is low, making tumors resistant to radiation therapy. It now appears that antiangiogenic therapy transiently improves a tumor's blood supply and oxygenation, making it more vulnerable to radiation therapy."

Although some animal studies have suggested that combining antiangiogenesis and radiation therapy can slow tumor growth, in others the treatment appeared to spur tumor growth. The current investigation was designed to resolve these conflicting results and to improve understanding of the cellular and molecular underpinnings of antiangiogenesis treatment. The MGH researchers implanted human brain tumor tissue into mice that were then treated with various combinations of an angiogenesis inhibitor called DC101 and radiation therapy.

DC101 alone produced a minor delay in tumor growth, and radiation alone produced a more significant growth delay. But of five different schedules of combined treatment, only giving radiation from 4 to 6 days after initiation of DC101 therapy resulted in a synergistic effect that was greater than simply adding the effects of both treatments. Measurement of the oxygen levels within tumor tissue supported the theory that DC101 improves oxygen delivery to the tumor during the same time period, with hypoxia (oxygen starvation) almost eliminated on day 5 but returning by day 8.

To better understand the mechanism behind these changes, the researchers conducted several detailed analyses of the tumor tissue. They observed a shift toward more normal blood vessels that were smaller and less disfigured after DC101 treatment and also found that these vessels had been stabilized by the recruitment of pericytes cells that normally help to support blood vessel walls. Mirroring the pattern of oxygen supply, pericyte coverage of blood vessels peaked around day 5 and then fell off by day 8.

The investigators also showed that greater pericyte coverage was the result of more pericytes being attracted to the tumor vessels, rather than the removal of pericyte-poor vessels as some researchers had assumed. Measurement of a factor known to be involved in pericyte recruitment found that its levels were temporarily increased after DC101 treatment. Examination of the effects of DC101 on vascular cells' basement membrane, which becomes abnormally thick in tumors, indicated that the membrane was thinner during the day-2-to-day-5 time period and also showed that this improvement resulted from the increased activity of specific enzymes.

One crucial result of these findings is alleviation of the concern that reducing a tumor's blood supply would actually worsen hypoxia and increase resistance to radiation therapy. "The success of this treatment approach depends on carefully scheduling when radiation is administered to take the greatest advantage of this window of vascular normalization," says Jain, who is Cook Professor of Tumor Biology at Harvard Medical School. His group plans further studies to determine how these results could be applied to treatment of cancer patients.

Additional authors of the current study are co-first authors Frank Winkler, MD, PhD, and Sergey Kozin, PhD, along with Ricky Tong, Sung-Suk Chae, PhD, Michael Booth, PhD, Igor Garkavtsev, MD, PhD, Lei Xu, MD, PhD, Dai Fukumura, MD, PhD, Emmanuelle di Tomaso, PhD, and Lance Munn, PhD, all of the Steele Laboratory at MGH; and Daniel Hicklin, PhD, of ImClone Systems Incorporated in New York.

Use of iNKT cells boosts tumor vaccination strategy

Thu, 16 Dec 2004 17:51:00 PST

( from http://www.rxpgnews.com ) T cell responses to natural infection are orders of magnitude greater than those observed in cancer patients in response to current vaccination protocols. Optimizing tumor vaccination protocols will require a deeper understanding of the signals that the immune system coordinates in order to respond to pathogenic infection. In the December 15 issue of the Journal of Clinical Investigation, Vincenzo Cerundolo and colleagues from the University of Oxford report a vaccination approach in mice in which intravenous delivery of a protein antigen plus a type of NK T cells, known as iNKT cells, enhanced the immune response and cleared an established tumor.

The authors demonstrate that the approach is effective when the vaccine is delivered orally or intravenously and could be exploited in future vaccination protocols aimed at eliciting immune responses against cancer and infectious diseases.

Cloned gene from sea animal may prove key in cancer drug development

Sat, 11 Dec 2004 18:36:00 PST

( from http://www.rxpgnews.com ) Researchers at Scripps Institution of Oceanography at the University of California, San Diego, and their colleagues have taken a significant step forward in developing a new method to produce drug compounds with potential to treat various types of cancer.

In the current issue of the journal Chemistry and Biology, scientists at Scripps, the University of Minnesota and the Life Sciences Institute describe the development of "bryA," a gene that could help solve problems associated with the production of anticancer agents originally discovered in the marine invertebrate Bugula neritina.

"To be able to show that this gene really exists has been the Holy Grail for the last 10 years," said Scripps Professor Margo Haygood, a coauthor of the paper. "This takes us beyond just suspecting that a bacteria might be involved to actually having a gene that looks like the right thing."

Certain marine invertebrates such as Bugula neritina, a brown bryozoan animal with stringy tufts, live in a symbiotic relationship with bacteria that act as a chemical defense mechanism for the host animal.

In 2001, Haygood and other scientists in her Scripps laboratory found that such bacteria living in Bugula neritina were the source of bryostatins, a family of chemical compounds being closely studied for their potential as anticancer pharmaceuticals in leukemia, lymphoma and several cancers including colon, breast, ovarian and prostate.

One of the main obstacles impeding widespread bryostatin production is lack of a practical and economically viable method of producing the compounds. The bacteria cannot be grown in laboratories. And collecting vast numbers of the animals at sea would be environmentally destructive.

One way of solving this dilemma is to clone the genes involved in natural bryostatin development. In the Chemistry and Biology paper, the researchers describe the process by which they cloned a large complex of genes and singled out bryA, a gene for a catalyst the authors propose is active in bryostatin biosynthesis.

The researchers say it appears that bryA may synthesize a portion of the pharmacologically active component of bryostatin and therefore may be useful in developing clinically useful bryostatin byproducts.

"The isolation of bryA represents a significant step forward inunderstanding bryostatin biosynthesis and eventually harnessing bry genes to produce bryostatins and derivatives inexpensively and in abundant quantities," the authors write in the paper, one of the first studies that describes such a cloning achievement from a marine symbiont organism.

Haygood and members of her laboratory are now moving the research forward by attempting to use bryA to extract laboratory-developed bryostatin compounds.

Most cancer drugs work by killing rapidly growing cells, in many cases interfering with the body's normal processes. Bryostatin seems to be effective by "flipping a switch" that controls how cells behave in the body. In the case of leukemia, for example, it seems to bring the cells "to their senses" and make them behave like normal blood cells.

In addition to Haygood, research coauthors include Mark Hildebrand, Laura Waggoner, Sebastian Sudek, Scott Allen and Christine Anderson of Scripps; and Haibin Liu and David H. Sherman of the Life Sciences Institute (Sherman was formerly at the University of Minnesota). Haygood is a member of Scripps's Marine Biology Research Division and Center for Marine Biotechnology and Biomedicine and the Rebecca and John Moores UCSD Cancer Center.

###

The research was supported by the National Institutes of Health and the Department of Defense.

First integrated immune cell response promises hope in cancer vaccine research

Thu, 04 Nov 2004 00:47:00 PST

( from http://www.rxpgnews.com ) There are many therapeutic cancer vaccines designed to harness the immunological system to limit the growth or spread of cancer under investigation in early-phase clinical trials. However, the vast majority are being developed with little or no immunological monitoring to determine whether and how the human immune system is responding to the vaccine being studied. The Cancer Vaccine Collaborative (CVC), a partnership established by the Cancer Research Institute in New York and the international Ludwig Institute for Cancer Research (LICR), has announced that it is the first to demonstrate that vaccination with a cancer-specific recombinant protein antigen has successfully induced a fully integrated immunological response in humans.

In a Phase I clinical trial conducted by the CVC in conjunction with GlaxoSmithKline (GSK), patients with non-small cell lung cancer received a vaccine of recombinant protein, MAGE-3, which was discovered at the LICR Branch in Brussels, and AS02B, one of GSKs immunological adjuvants. MAGE-3 is a member of a family of highly cancer-specific antigens present on a wide variety of tumors, and AS02B stimulates the bodys immunological response to the protein. Most of the antigen-specific cancer vaccines that are currently in early-phase clinical trials use protein fragments called peptides. In contrast, the CVC cancer vaccine contains the full-length protein antigen. Infectious disease vaccines routinely used today also contain full-length proteins, and not peptides.

Induction of vaccine-specific antibodies and CD8 T cells, which destroy tumor cells carrying the antigen, have been previously observed in trials of cancer vaccines. However, antibodies and CD8 cells represent only two parts of the complex immunology equation. The results of the CVC study, published in the Journal of Immunology, showed that in the majority of patients the vaccine induced CD4 T cells, which function to enhance CD8 T cell activity and, most importantly, act to sustain the attack on the cancer antigen for longer periods of time. The team used a new method, developed in the CVC laboratories in New York, which allows researchers to monitor, for the first time, all three major components of the immunological response to cancer vaccines. The patients in the study are now being followed to measure their long-term clinical response to the vaccine, and to assess whether vaccine booster shots are necessary to maintain their immunization.

We have a mantra for cancer vaccine development, says Dr. Lloyd J. Old, Director of the Cancer Vaccine Collaborative, and a senior author on the paper. You wont know how to vaccinate until you know how to immunize. And you wont know how to immunize until you know how to monitor. Being able to monitor the full set of immunological responses allows us to specifically test different antigens and vaccine component combinations, like the addition of AS02B, and identify therapeutic responses that are associated with immune responses.

The necessity of immunological monitoring to enable rational vaccine development was echoed by Dr. Herbert Oettgen of Memorial Sloan-Kettering Cancer Centers Clinical Immunology Service. We should keep in mind that every modern vaccine developed for infectious diseases has gone through a rigorous progression of testing components and monitoring the immune responses to establish strong and sustained immunization in humans. And yet cancer vaccines have often been given to patients without having demonstrated that they illicit a strong immune response.

Dr. Jill ODonnell-Tormey, the Executive Director of the Cancer Research Institute, says that the CVC has already begun to apply the new monitoring method to their clinical trials at CVC Centers in Australia, Belgium, Germany, Japan, Switzerland, the United Kingdom, and the USA. The ability to monitor is really making a big difference to our work. We are now using a systematic, coordinated approach to vaccine development, by comparing the immunological responses produced by single vaccine variables being tested in parallel at each of our different sites. We believe that this approach will yield cancer vaccines with the greatest efficacy, and in a much shorter time than the conventional approach of trying variables sequentially with limited monitoring of responses.

- END -

The published study was supported by the Cancer Research Institute and sponsored by the Ludwig Institute for Cancer Research, under the auspices of the Cancer Vaccine Collaborative. The clinical component of the study was conducted at the Weill Medical College of Cornell University. The CVC team was comprised of researchers from the New York Branch of the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center, and the Departments of Cardio-Thoracic Surgery and Pathology at Weill Medical College of Cornell University.

For further details, please contact:

Cancer Research Institute:
Ms Lynne Harmer, Director of Grants Administration
lynneh@cancerresearch.org 212 688 7515

Ludwig Institute for Cancer Research:
Dr. Sarah White, Communications Officer
swhite@licr.org 212 450 1543

Trials of Cyclooxygenase (COX) Inhibitors for Cancer Prevention and Treatment

Thu, 12 Feb 2004 13:56:00 PST

( from http://www.rxpgnews.com ) Numerous compounds are examined by the National Cancer Institute (NCI) for their potential to prevent or treat cancer. One class of compounds, cyclooxygenase (COX) inhibitors, is currently being tested in both prevention and treatment clinical trials. Epidemiologic studies have shown that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen to treat conditions like arthritis, have lower rates of colorectal polyps, colorectal cancer, and death due to colorectal cancer. NSAIDs block cyclooxygenase enzymes, which are produced by the body when there is inflammation and are also produced by precancerous tissues. Inhibition of COX-2 may help treat and prevent cancer, while inhibition of COX-1 may induce certain medical problems, like stomach bleeding, that occur when NSAIDS are taken regularly for long periods of time.

Pharmaceutical companies have created NSAIDs that block only COX-2; one of them, celecoxib (CelebrexTM), manufactured by Pfizer, Inc., New York, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of both osteoarthritis and adult rheumatoid arthritis (diseases in which the joints are inflamed) in December 1998. Because over a decade of scientific work has suggested the potential of COX-2 inhibitors to prevent and treat cancer, the National Cancer Institute (NCI) has clinical trials under way to look at the efficacy and safety of these drugs.

NCI's Division of Cancer Prevention (DCP) began its studies with celecoxib with a trial in people with Familial Adenomatous Polyposis (FAP). Patients with FAP develop hundreds to thousands of precancerous polyps (adenomas) throughout the colon and rectum. Left untreated, nearly all FAP patients develop colorectal cancer by their 40s and 50s. The primary treatment for FAP is surgical removal of most or all of the colon and rectum with subsequent surveillance of any remaining colorectal segment. In an NCI-sponsored trial, celecoxib helped reduce the number of colon polyps in patients with FAP. The results of this study were published in the New England Journal of Medicine on June 29, 2000, and led to FDA-approval of celecoxib as an adjunctive drug (an accessory or auxiliary agent) that could be added to the standard of care in people with FAP.

As of October 2004, DCP sponsored 23 trials of varying sizes to test the potential of celecoxib to prevent cancer in a number of organ sites. These trials range in size from under 10 participants to more than 2,000 and aim to prevent bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. The majority of these trials are in collaboration with Pfizer, Inc.

Additionally, to examine potential benefits of COX-2 inhibitors for the treatment of patients with cancer, NCI's Division of Cancer Treatment and Diagnosis (DCTD) is sponsoring almost 20 trials of varying sizes with celecoxib. The majority of these studies are small phase I or II clinical trials in cancers such as pancreatic, breast, ovarian, non-small cell lung, and solid tumors. DCTD also is sponsoring two ongoing randomized phase III clinical trials: the first trial compares two chemotherapy agents, exemestane vs anastrozole, in postmenopausal women with estrogen receptor-positive primary breast cancer; the second trial compares several chemotherapy agents in node-negative breast cancer patients. Both phase III trials randomized women to either those taking celecoxib or not taking celecoxib, in addition to the agents mentioned above.

On September 30, 2004, the COX-2 inhibitor rofecoxib (VioxxTM) was removed from the market after a two-fold increased risk of cardiovascular toxicities was identified in people taking the drug for 18 months within a trial to prevent colon adenomas. The sponsor of the 2,600 person trial, Merck & Co., Inc. (New Jersey), sent a letter to physicians announcing the removal of the drug and explaining the action. NCI's Division of Cancer Prevention had planned to undertake a lung cancer prevention trial using rofecoxib, but has abandoned that plan following the withdrawl of rofecoxib.

On October 18, 2004, Pfizer, Inc. announced it will initiate a trial of celecoxib users that will last for two years. The study will examine inflammation and cardiovascular events in osteoarthritis patients at high risk for heart disease. It will be conducted at major universities and hospitals around the world and is expected to start early in 2005, enrolling 4,000 patients who have had a recent heart attack and who also have a history of osteoarthritis.

Based on the safety concerns reported in the rofecoxib trials, and the possibility that these concerns may extend to other COX-2 inhibitors such as celecoxib, NCI is rapidly reviewing data in both prevention and treatment trials. All of NCI's large trials have Data Safety and Monitoring Boards which regularly meet in person and review data on adverse events monthly. Cardiovascular experts have been added, where appropriate, to evaluate adverse cardiovascular events.