RxPG News : Brain

Signaling pathway discovered which may help find treatment for glioblastoma multiforme

Sat, 14 Aug 2010 21:28:59 PST

( from http://www.rxpgnews.com ) Malignant gliomas are the most common subtype of primary brain tumor – and one of the deadliest. Even as doctors make steady progress treating other types of solid tumor cancers, from breast to prostate, the most aggressive form of malignant glioma, called a glioblastoma multiforme or GBM, has steadfastly defied advances in neurosurgery, radiation therapy and various conventional or novel drugs.

But an international team of scientists, headed by researchers at the Ludwig Institute for Cancer Research (LICR) at the University of California, San Diego School of Medicine, reports in the August 15 issue of Genes & Development that they have discovered a new signaling pathway between GBM cells – one that, if ultimately blocked or disrupted, could significantly slow or reduce tumor growth and malignancy.

More than other types of cancer, GBMs are diverse assemblages of cell subtypes featuring great genetic variation. Anti-cancer therapies that target a specific mutation or cellular pathway tend to be less effective against such tumor heterogeneity.

"These myriad genetic alterations may be one of the primary reasons why GBMs are so lethal," said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and an associate investigator at the San Diego branch of the LICR.

Even with maximum treatment effort, the median patient survival rate for a diagnosed GBM is nine to 12 months – a statistic that has not changed substantially in decades.

However, Furnari, along with postdoctoral fellows Maria-del-Mar Inda and Rudy Bonavia, and Webster Cavenee, PhD, professor of medicine and director of the San Diego LICR branch, and others noted that in GBMs only a minority of tumor cells possess a mutant form of the epidermal growth factor receptor (EGFR) gene. These cells drive the tumor's rapid, deadly growth. "Most GBM tumor cells express wild-type or normal EGFR," said Furnari. "Yet when expressed by itself, wild-type EGFR is a poor oncogene."

The scientists discovered that tumor cells with mutant EGFR secrete molecules that cause neighboring cells with wild-type EGFR to accelerate their tumorigenic growth. "The mutant cells are instructing other less malignant tumor cells to become more malignant," said Furnari.

This signaling pathway between GBM tumor cells was not known and presents a new and potentially promising chink in the armor of glioblastomas. "If we can inhibit or block this cellular communication, the tumor does not grow as quickly and may be more treatable," Furnari said. Researchers have already identified two molecules that appear to trigger EGFR activity on non-mutant tumor cells.

The findings may also provide clues in the bigger picture of how GBMs and other cancers survive and thrive. "There are other types of mutations and growth factor receptors in tumors," Furnari said. "We need to look at how they communicate. Historically, brain tumor research has focused upon the most abundantly expressed mutations, but this research suggests minority mutations play very important roles as well."

The researchers' next step will be to create a mouse model with mixed cell glioblastoma that can be used to test different therapeutics, inhibitors and blocking agents.

Electronic nose potent new weapon against brain cancer

Thu, 18 Jun 2009 13:23:51 PST

( from http://www.rxpgnews.com ) An electronic 'nose' developed by NASA for air quality monitoring on Space Shuttle Endeavour can also act as a potent new weapon against brain cancer.

The 'nose' can detect odour differences in normal and cancerous brain cells, opening up new possibilities for neurosurgeons in the fight against the condition.

Neurosurgeons from the City of Hope Cancer Centre, along with scientists from the Brain Mapping Foundation - in West Hollywood and Jet Propulsion Laboratory -, used NASA's electronic 'nose' to investigate the role of cellular odour in cellular trafficking, brain cancer metastasis and stem cell migration.

The 'electronic nose', which is to be installed on the International Space Station to automatically monitor the station's air, can detect different contaminants, some with concentrations as low as one part per million.

In a series of experiments, the BMF used NASA's electronic nose to sniff brain cancer cells and cells in other organs. These experiments will help pave the way for more sophisticated biochemical analysis and experimentation, said a NASA release.

Babak Kateb, study co-author said: 'This pilot study lays the groundwork for future research that may help us better understand cellular trafficking, contribute to designing better approaches for the detection and differentiation of brain cancer, and understand the pathophysiology of intracranial gliomas.'

The results will be presented at the sixth Annual World Congress for Brain Mapping & Image Guided Therapy at Harvard Medical School, Aug 26-29.

Neuroblastoma treatment- adding tumor-specific receptor to cytotoxic T cells with EBV receptor

Sun, 02 Nov 2008 15:51:27 PST

( from http://www.rxpgnews.com ) Adding an artificial tumor-specific receptor to immune system cells called T-lymphocytes that target a particular virus extended and improved the cells' ability to fight a form of childhood cancer called neuroblastoma, said researchers form Baylor College of Medicine and Texas Children's Hospital in a report that appears online in the journal Nature Medicine.

"This is a way to convert a naturally occurring problem into a benefit in treating cancer," said Dr. Malcolm Brenner, director of the Center for Cell and Gene Therapy at BCM, TCH and The Methodist Hospital, and professor of pediatrics and medicine at BCM. He and his colleagues reported on using the new treatment in 11 patients with recurring neuroblastoma. "For the first time, we started to see tumor responses. We have one complete remission and others who have had stable disease for more than a year," said Brenner.

The patients responded after only the one infusion of cells because they last a long time in the body and their numbers can increase, said Brenner.

Previous attempted to use T-lymphocytes with an artificial receptor directed to tumor cells proved disappointing because they disappeared from the body too quickly to have an anti-cancer effect. However, cytotoxic T cells that already have a natural receptor for the Epstein-Barr virus are continually activated by the presence of the virus, which is never eliminated from the body.

Brenner and his group added to these T-lymphocytes a particular receptor for a protein called diasialoganglioside GD2, which is found in human neuroblastoma cells.

"We took the T-lymphocytes' with specificity for Epstein-Barr and added another receptor," said Brenner. "In effect they trampoline off the virus and onto the tumor."

Thus these cytotoxic T-lymphocytes remain in the body because they are constantly stimulated by the virus. Their artificial antigen receptor enables them to latch onto and kill the cancer cells.

When the researchers put the artificial receptor into both ordinary T-lymphocytes and those that are stimulated by the virus into the 11 patients, they found that the cancer directed cells stimulated by the Epstein-Barr virus lasted as long as 18 months and at higher levels than the other cells.

Neuroblastoma is a tumor of primitive cells that go on to form the sympathetic nervous system. Apart from brain tumors, it is the most common solid cancer of children, and accounts for 7 percent of the total. In two-thirds of cases, it is not diagnosed until it has already spread to other parts of the body.

He and his colleagues hope to improve the treatment to make the T-lymphocytes more potent cancer killers, he said. One way would be to add specific receptors for proteins that allow the T-lymphocytes to avoid the immune-dampening effects of the cancers. Another might be to give the treatment right after the patients receive a stem cell transplant. At that time, the number of tumor cells would be at its lowest and there would be a lot of signals telling the T-lymphocytes to increase in number.

Within the next year, they plan to add receptors for other cancers to the virus-specific T-cells and see if they get the same cancer-fighting effect.

Significant vaccine-enhanced immune response in malignant brain tumour

Tue, 15 Jul 2008 01:21:44 PST

( from http://www.rxpgnews.com ) Researchers conducting a clinical trial of a dendritic cell vaccine designed to fight malignant brain tumors called glioblastoma multiforme (GBM) have found a correlation between the "intensity" of a patient's immune response and clinical outcome, according to an article in the July 15 issue of the journal Cancer Research.

While other studies have suggested a link, this is believed to be the first to show direct and continual proportionality between the strength of anti-tumor responses and clinical benefits in cancer patients. This also may be the first documentation of a definite immune response/patient outcome correlation that can be credited to tumor-altering therapeutic interventions.

"Fifty-three percent of patients in our study exhibited a significant vaccine-enhanced immune response. Compared to non-responders or those with limited responses, the vaccine responders had significantly longer times to tumor progression and longer survival," said Keith L. Black, M.D., chairman of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute. Black is one of the article's authors.

The study also substantiates a finding previously reported by the researchers: Dendritic cell vaccination and chemotherapy work synergistically to improve treatment. Time to tumor progression increased significantly when vaccination was followed by chemotherapy, compared to vaccination alone.

"No other vaccine trial in cancer patients has shown the kind of progressive correlation between immune responses and clinical outcomes that we found," said Christopher J. Wheeler, Ph.D., research scientist at the MDNSI and the article's first and corresponding author. "We looked at whether the correlation was present after vaccination alone or after post-vaccine chemotherapy. It was evident only after post-vaccine chemotherapy. This leads us to believe that while T-cell activity may not result in net destruction of the tumor it is fundamentally changing the tumor into one that is predominantly comprised of chemosensitive cells rather than chemoresistant cells."

The findings also appear to give scientists a way to more quickly evaluate future vaccine-related research.

"The demonstration that the magnitude of immune response is directly related to survival of patients gives us a very good tool or 'surrogate marker' for clinical benefit. If we can improve the immune response of our vaccine, we can anticipate that the clinical benefit will be improved as well. This allows us to fine-tune our vaccine in more of a real-time way," said John S. Yu, M.D., director of Surgical Neuro-oncology at Cedars-Sinai, principal investigator of the clinical trial and senior author of the article.

This study centered on the immune responses of 32 patients enrolled in a Phase II clinical trial. Seventeen patients had a significant positive response after three vaccinations; 15 showed no such responsiveness. Average time to tumor progression (based on when tumor volume increased by about 25 percent on MRI scans) was about 308 days among responders, compared to 167 days for non-responders. Average length of survival (based on date of death or date of last contact with surviving patients) was about 642 days (about 21 months) among responders, compared to 430 days (about 14 months) for non-responders.

Forty-one percent of vaccine responders, compared to seven percent of non-responders, survived at least two years. All patients in the trial had longer time to progression and longer time of survival, on average, than patients undergoing standard treatment without vaccination, although their pre-vaccine disease courses were similar.

The vaccine was first used experimentally in patient treatment in May 1998, and numerous studies have been conducted to fine-tune the therapy and combine it with other cancer-killing treatments.

Upon founding the Maxine Dunitz Neurosurgical Institute in 1997, Black led the development of the dendritic cell vaccine because gliomas and other cancer cells are not readily detected or attacked by the immune system. Dendritic cells are the immune system's most powerful antigen-presenting cells – those responsible for helping the immune system recognize invaders.

When a tumor is surgically removed, proteins are collected, cultured and introduced in a Petri dish to dendritic cells taken from the patient's blood. The new, "educated" dendritic cells are then injected into the patient where they are intended to recognize and destroy lingering tumor cells. Patients receive three vaccinations at two-week intervals. A fourth vaccination is given six weeks after the third.

Simultaneous implantation of radioactive seeds and chemotherapy wafers promising in glioblastoma multiforme treatment

Sun, 20 Jan 2008 09:31:57 PST

( from http://www.rxpgnews.com ) In the battle against malignant brain tumors, dual implantation of radioactive seeds and chemotherapy wafers following surgery showed promising results in a study led by specialists at the Neuroscience Institute at the University of Cincinnati (UC) and University Hospital.

The study, published in the February issue of the Journal of Neurosurgery, revealed that patients treated with simultaneous implantation of radioactive seeds and chemotherapy wafers following removal of glioblastoma multiforme (GBM) experienced longer survival compared with patients who had implantation of seeds or wafers alone.

The study was the first ever to explore the combination treatment in patients suffering from recurrent GBM. The early phase trial involved 34 patients, all of whom underwent the same treatment. No patients received a placebo. The study’s purpose was to assess the safety and effectiveness of the highly localized, combination therapy.

The median survival was 69 weeks, and nearly a quarter (eight) of the study’s patients survived two years. In comparison, patients with recurrent GBM who undergo conventional treatment (chemotherapy) have a median survival of approximately 26 weeks.

“Treatment of recurrent GBM presents a major challenge to neurosurgeons and neuro-oncologists,” said investigator Ronald Warnick, MD, chairman of the Mayfield Clinic and professor of neurosurgery at UC. “Glioblastoma is an aggressive, highly malignant tumor with unclear boundaries. Because of its diffuse nature, surgeons are unable to remove it completely, and it regrows in the majority of patients. Our aim is to find a way to keep the infiltrating glioblastoma cells from growing into adjacent, healthy tissue.”

Because most GBM tumors recur within two centimeters of the initial tumor margin, Warnick and his team have focused their efforts on highly localized treatment.

Previously they studied the implantation of permanent, low-activity iodine-125 seeds following the surgical removal of the tumor. The seeds, housed in a titanium casing filled with iodine-125 (a radioisotope of iodine) are the size of grains of rice. The seeds are left in the brain cavity permanently, and radiation is delivered for six months.

Other institutions have studied implantation of chemotherapy wafers, which are the size of a nickel. The wafers contain BCNU (carmustine), a standard form of chemotherapy. The wafers are placed along the surface of the brain following removal of the tumor.

Combining radiation seeds and chemotherapy wafers was a logical next step, Warnick said. The combination of seeds and wafers “appears to provide longer survival” compared with studies of seeds and wafers alone, he said, and “disease progression also seems to be further delayed.”

Warnick cautioned that the effectiveness of the combination therapy is not definitive, because the study did not include a control group.

In the most notable downside to the dual therapy, brain tissue death developed in nearly 25 percent of patients and appeared to be higher than in treatment with seeds or wafers alone. The tissue death was treated successfully with surgery or hyperbaric oxygen therapy, however, and did not affect survival.

Future studies will involve using a combination of seeds and wafers to treat patients newly diagnosed with GBM, Warnick said.

KetoCal diet: A non-invasive way to deal with malignant brain cancers

Wed, 21 Feb 2007 08:05:28 PST

( from http://www.rxpgnews.com ) Boston College biologists have identified an alternative, diet-based method of treating brain cancer that does not involve administering toxic chemicals, radiation or invasive surgery.

The biologists found that KetoCal, a commercially available high-fat, low-carbohydrate diet designed to treat epilepsy in children, can significantly decrease the growth of brain tumors in laboratory mice. Moreover, the diet significantly enhanced health and survival rates relative to mice in control groups who consumed a standard low-fat, high-carbohydrate diet.

The findings were based on a study published this week in the online journal Nutrition & Metabolism.

KKetoCal represents a novel alternative therapy for malignant brain cancer,?said Boston College Biology Professor Tom Seyfried, who conceived and supervised the study. wWhile the tumors did not vanish in the mice who received the strict KetoCal diet, they got significantly smaller and the animals lived significantly longer. And compared to radiation, chemotherapy and surgery, KetoCal is a relatively inexpensive treatment option.

Malignant brain cancer is one of the most lethal types of cancer in adults and is the second leading cause of cancer death in children. Many current ways of treating the disease fail to provide long-term management because they ineffectively target tumor cells and harm the health and vitality of normal brain cells.

The KetoCal diet gets around this dilemma by essentially starving the brain tumor cells of the sugary molecules on which they rely for growth and survival. Because of its special composition, the diet deprives the tumor cells of the glucose they need; at the same time, the diet provides normal brain cells with ketones, a class of organic compounds they can metabolize effectively but the tumor cells cannot.

In their experiment, the BC team surgically implanted two different kinds of tumors into the brains of male mice. The mice were then divided into three groups. One group was fed a high-carbohydrate mouse chow, one was given unlimited amounts of KetoCal, and the final group was given KetoCal in a restricted dosage.

The researchers found that in the mice on the restricted diet, KetoCal decreased the growth of brain tumors by between 35 percent and 65 percent. Moreover, survival rates were higher in the mice on the restricted diet.

TThis preclinical study indicates that KetoCal is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer,?the researchers wrote.

KetoCal is manufactured by Nutricia North America. The study authors report they have no financial interests in the company, although it did provide the KetoCal used in the experiments as a gift.

The journal articles lead author is Weihua Zhou, a research technician in the Boston College Biology Department. Co-authors include Seyfried, Purna Mukherjee, Michael Kiebish, William Markis and John Mantis

Bevacizumab holds promise for gliomas

Tue, 20 Feb 2007 07:20:13 PST

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

Avastin may be effective in treating gliomas because these tumors have a high concentration of vascular endothelial growth factor, a protein that stimulates development of new blood vessels in a process known as angiogenesis.

Avastin, a relatively new type of drug that shrinks cancerous tumors by cutting off their blood supply, can slow the growth of the most common and deadly form of brain cancer, a pilot study conducted at Duke University Medical Center has found.

The study marks the first time that Avastin has been tested against brain tumors, the researchers said. The drug, whose chemical name is bevacizumab, currently is used to treat lung and colorectal cancers.

The researchers tested the effectiveness of Avastin in conjunction with a standard chemotherapy agent in patients with recurrent cancerous brain tumors called gliomas. They found that the two drugs together halted tumor growth up to twice as long as comparative therapies. Though gliomas remain incurable in nearly all cases, the combined drug therapy may buy precious time and preserve physical and mental function longer for patients facing this grim diagnosis, the researchers said.

"These results are exciting because of the possible implications for a patient population that currently has the poorest possible prognosis going into treatment, those with malignant brain tumors that have recurred after initial treatment," said James Vredenburgh, M.D., a brain cancer specialist at Dukes Preston Robert Tisch Brain Tumor Center and lead researcher on the study.

The findings will appear in the Feb. 20, 2007, issue of the journal Clinical Cancer Research. The study was funded by the National Institutes of Health, the Preston Robert Tisch Brain Tumor Research Fund, the Bryan Cless Research Fund and Genentech, the maker of Avastin.

Duke currently is participating in a large, multi-institutional study of Avastin to corroborate the results of this initial study, Vredenburgh said.

Kate Carr, president and chief executive officer of Accelerate Brain Cancer Cure, a not-for-profit organization that supports research to hasten a cure for brain cancer, said, "The results of this initial study are very encouraging and we are now excited to learn the findings of the larger study, that, it is hoped, will lead to an approved therapy for patients with brain cancer."

In the pilot study, the researchers found that dual therapy with Avastin and the chemotherapy drug irinotecan either shrank the tumors or restricted their growth in nearly all cases for up to three months longer than comparative therapies. Three months is a significant advance when dealing with these aggressive tumors, Vredenburgh said; common current treatment normally offers only six to 12 weeks of halted growth before the tumor grows and spreads, ultimately destroying cognitive and physical function and leading to death.

Approximately 18,000 people are diagnosed with gliomas in the United States each year, making them the most common and most deadly malignant tumors of the central nervous system. Gliomas are difficult to treat because they grow quickly and occur behind the blood-brain barrier, a natural protective layer around the brain that prevents materials carried in the bloodstream -- including medicines -- from reaching the brain and spinal cord.

Life expectancy after diagnosis of a stage IV glioma -- the most aggressive kind of the cancer -- is eight to 15 months, Vredenburgh said. Individuals diagnosed with a stage III glioma, which is slightly less aggressive, survive 16 to 24 months on average. When the tumor returns after initial treatment -- which usually includes surgery, chemotherapy and radiation -- the prognosis is even more grim, with an average life expectancy of three to nine months.

"When the tumor recurs after treatment, there are no standard therapies," Vredenburgh said. "This study may lead to options where there previously were none."

Avastin may be effective in treating gliomas because these tumors have a high concentration of vascular endothelial growth factor, a protein that stimulates development of new blood vessels in a process known as angiogenesis. New blood vessels spur a tumors growth and ability to spread, so researchers are interested in cutting off angiogenesis to slow tumors down. Avastin is an anti-angiogenesis drug that works by choking off the blood supply to these prolific blood vessels.

"What makes these tumors so deadly might actually be what also makes them susceptible to this exciting new therapy," Vredenburgh said.

The 32 patients who participated in this study had been diagnosed with stage III or stage IV recurrent gliomas. Sixty-three percent of the patients saw their tumors shrink by at least 50 percent in the first 12 weeks of the study and 38 percent were progression-free at six months, meaning their tumors had not grown, Vredenburgh said.

"Going forward, we will also explore the efficacy of this treatment in newly diagnosed patients," he said. "Ultimately, our hope is that this will offer a real weapon in what is now a very limited arsenal for treating a very challenging cancer."

'Gateway' gene discovered for brain cancer

Wed, 14 Feb 2007 10:36:24 PST

( from http://www.rxpgnews.com ) Researchers have discovered that the same genetic regulator that triggers growth of stem cells during brain development also plays a central role in the development of the lethal brain cancer malignant glioma. In experiments on mice with such gliomas, they showed that knocking out the function of a particular regulatory protein, Olig2, almost completely eliminated tumor formation.

The researchers said their findings suggest that targeting Olig2 could offer a potential avenue for treatment that would kill tumor cells without affecting normal tissue.

Dana-Farber Cancer Institute investigators Charles Stiles and David Rowitch and their colleagues reported their findings in the February 15, 2007 issue of the journal Neuron, published by Cell Press.

Olig2 is a "transcription factor"a protein that regulates the activity of genes. Prior studies had indicated that it plays a central role in enabling neural stem cells to replicate during embryonic brain development. Also, studies have suggested that brain tumors might arise from aberrant neural stem cells or the neural progenitor cells to which they give rise.

Analyzing tissue from human gliomas, Stiles, Rowitch, and their colleagues discovered that Olig2 is activated in the stem and progenitor cells found in the tumors. In a mouse model of malignant glioma, they found that knocking out Olig2 function prevented tumor formation in 91 percent of the animals.

Their analysis of the role of Olig2 in both tumor cells and normal neural stem cells revealed that it plays a key role in enabling cell growth. Specifically, they found that Olig2 represses the gene for a cell-replication "brake" called p21, which normally inhibits cell growth. Thus, they concluded that Olig2 is a "unifying feature of normal cell cells and malignant glioma" and a "gateway" gene for brain tumor development.

"Lineage-restricted pathways that regulate brain tumor behavior may represent more specific therapeutic targets with little potential to affect off-target cell types," commented the researchers.

"Brain tumors remain a major cause of cancer-related death despite advances in surgery, imaging, and conventional treatment modalities," they wrote. "This emphasizes the need to develop novel medical strategies based on a comprehensive understanding of the biological mechanisms underlying gliomagenesis."

They wrote that "our findings identify this core transcriptional regulator as an important candidate for antitumor therapeutics." While transcription factors are not generally considered useful targets for anti-cancer drugs, there are multiple ways that Olig2 could be inhibited, as well as ways to target other components of the regulatory pathway by which it exerts its influence on tumor growth, wrote the researchers.

Regulatory Approval for New Cotara(R) Brain Cancer Clinical Trial

Fri, 13 Oct 2006 01:17:00 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, a biopharmaceutical company with a portfolio of innovative, clinical stage products for the treatment of cancer and hepatitis C virus infection, today announced that it has received regulatory approval in India for a new clinical trial of its lead tumor necrosis therapy (TNT) agent Cotara(R). The trial is designed to test the safety and efficacy of Cotara in patients with glioblastoma multiforme, a deadly form of brain cancer. Cotara is currently being studied in a multi-center U.S. glioblastoma trial. Previous studies using Cotara to treat brain cancer have produced encouraging results, and Peregrine expects that positive data from this trial in combination with data from the ongoing U.S. clinical trial should provide the foundation for planning the future development and commercialization of Cotara.

The new safety and efficacy study is expected to be an integral part of Peregrine's overall Cotara brain cancer development program. It will be conducted according to internationally accepted ICH GCP guidelines at up to seven clinical centers and is expected to enroll up to 40 patients with glioblastoma who have experienced their first relapse. Patients will receive a single infusion of the drug by convection-enhanced delivery (CED), an NIH-developed technique in which the drug is slowly administered directly into the glioblastoma tumor with great precision. The primary endpoints of the trial are to confirm safety and determine median survival time and median time to progression in Cotara-treated patients. Patient enrollment in the study is expected to be completed by the end of 2007.

"We believe this new clinical trial will be a cornerstone of our future plans to develop Cotara for the treatment of this deadly form of cancer," said Steven W. King, president and CEO of Peregrine. "We are moving this program forward in India because of the high level of experience of the participating neurosurgeons with CED delivery, the state-of-the-art facilities of the medical centers involved and the fact that the contract research organization overseeing the trial is highly experienced in successfully running similar glioblastoma trials with many of the investigators who will be involved with our study."

Mr. King added, "We have previously generated encouraging results using Cotara in this lethal cancer, and this study should allow us to evaluate the potential of the drug to extend patient survival more rapidly than we had originally anticipated. The new trial aims to provide clinical data in a timely manner that can be combined with the dosimetry and safety data we will be gathering from the ongoing U.S. study to guide the further clinical and commercial development of Cotara. We believe this trial could greatly expedite our Cotara brain cancer program based on the fact that some of the cancer centers we are working with routinely treat thousands of brain cancer patients each year, while major U.S. centers typically treat at most several hundred."

Global pharmaceutical companies including Pfizer, GlaxoSmithKline, Roche and Eli Lilly have been conducting an increasing number of major clinical trials in India in recent years, taking advantage of the country's world-class clinical research facilities that leverage India's large cadre of Western-trained medical personnel and enormous pool of patients eager to participate in clinical trials.

Cotara is an experimental new treatment for brain cancer that links a radioactive substance designed for medical uses -- a radioactive isotope -- to a targeted monoclonal antibody. This monoclonal antibody is designed to bind to a type of DNA that is exposed only on dead and dying cells. Solid tumors, including brain tumors, have a significant number of dead and dying cells at their center, and Cotara's targeting mechanism enables it to home in on these dying tumor cells, delivering its radioactive "payload" directly to these cells at the center of the tumor mass. Cotara thus literally destroys the tumor "from the inside out" with minimal radiation exposure to healthy tissue.

Cotara is delivered through a special method called convection-enhanced delivery (CED). CED uses a catheter to bypass the blood brain barrier and target the specific tumor site in the brain, directing Cotara to the tumor more precisely. This type of delivery has been shown to achieve up to a 10,000-fold greater concentration in local therapy exposure than conventional intravenous drug administration, while minimizing unwanted exposure.

In previous clinical studies Cotara has demonstrated encouraging results in a number of patients with advanced brain cancer. One study demonstrated a greater than 50% increase in median survival time in a group of patients suffering from late stage glioblastoma multiforme who were treated with Cotara. This was considered a promising development in this serious and deadly disease. Cotara is currently in a multi-center dosimetry and dose confirmation trial in glioblastoma patients being conducted by the New Approaches to Brain Tumor Therapy (NABTT), a consortium of leading U.S. academic brain cancer centers. Cotara has been granted orphan drug status and fast track designation by the U.S. Food and Drug Administration for the treatment of glioblastoma multiforme.

Lead exposure linked with brain cancer

Tue, 29 Aug 2006 03:13:00 PST

( from http://www.rxpgnews.com ) People who are routinely exposed to lead on the job are 50 percent more likely to die from brain cancer than people who are not exposed, according to a University of Rochester Medical Center study.

More than 18,000 brain and spinal cord tumors will be diagnosed in the United States this year. Yet little is known about what causes brain cancer; the only established risk factor is radiation, according to the American Cancer Society.

Results of other studies attempting to show a clear link between lead and cancer have been inconclusive. The new data, based on information from the U.S. Census Bureau and the National Death Index, may be the largest study ever to find a lead-cancer link. In doing so it provides further evidence that widespread environmental risk factors such as lead must be explored, said study author Edwin van Wijngaarden, Ph.D.

"If we are able to help explain the cause of even 1 or 2 percent of the total number of cases, that's important," said van Wijngaarden, an assistant professor and epidemiologist in the Department of Community and Preventive Medicine at the University of Rochester.

Published in the Sept. 1, 2006, issue of the International Journal of Cancer, the study computed the risk estimates for lead exposure and brain cancer from a census sample of 317,968 people who reported their occupations between 1979 and 1981. Van Wijngaarden was looking for evidence of an exposure-response trend, or a rise in cancer incidence or mortality associated with an exposure to a toxic substance. The goal among researchers who do this type of investigation is to identify preventable, environmental risk factors that might cause the gene mutations that lead to cancer.

Each occupation was classified into categories established by the National Cancer Institute. The NCI job matrix for lead is designed to estimate the likelihood of exposure and the intensity of exposure. It rates each occupation on a scale from zero (no exposure) to three (high exposure).

Gas station attendants from the 1970s and early 1980s, for example, were estimated to have a high probability of exposure, but only medium intensity of exposure because their direct contact with leaded gasoline was not as great as the potential for contact. The jobs with the highest probability and intensity of lead exposure were painters and automobile mechanics. But firefighters, engineers, automobile assemblers, truck drivers, plumbers, welders, and printers or typesetters were all among those individuals with some likelihood of lead exposure, according to the NCI matrix.

When Van Wijngaarden applied the matrix to nearly 318,000 people and followed their cancer rates for nine years, he found 119 brain cancer deaths. The death rate among people with jobs that potentially exposed them to lead was 50 percent higher than unexposed people, and the number of deaths was larger than in many previous studies, van Wijngaarden said. Other trends that emerged were slightly higher death rates among less educated and married individuals.

Scientists have suspected for years that lead is a carcinogen, which passes through the blood-brain barrier, making the brain especially sensitive to the toxic effects of lead. Van Wijngaarden is continuing his research with a pilot study to measure the actual bone-lead levels in people who have been diagnosed with brain tumors.

"My interest is in exploring the long-term implications of lead exposure," van Wijngaarden said. "Lately, a lot of the information about lead and its toxicity has focused on children. We do know that in young people it can cause acute illness and behavioral problems. But what is under appreciated, I believe, are the chronic health effects."

Synthetic scorpion venom delivers radioactive iodine to malignant gliomas

Sun, 30 Jul 2006 02:45:00 PST

( from http://www.rxpgnews.com ) A new method of delivering a dose of radioactive iodine using a man-made version of scorpion venom as a carrier targets deadly brain tumors called gliomas without affecting neighboring tissue or body organs. After a Phase I clinical trial conducted in 18 patients showed the approach to be safe, a larger Phase II trial is underway to assess the effectiveness of multiple doses.

Adam N. Mamelak, M.D., a neurosurgeon at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute, led the Phase I trial and is first author of an article in the August of the Journal of Clinical Oncology.

The key ingredient is TM-601, a synthetic version of a peptide, or protein particle, that naturally occurs in the venom of the Giant Yellow Israeli scorpion. TM-601 binds to glioma cells and has an unusual ability to pass through the blood-brain barrier that blocks most substances from reaching brain tissue from the bloodstream.

"We're using the TM-601 primarily as a carrier to transport radioactive iodine to glioma cells, although there are data to suggest that it may also slow down the growth of tumor cells. If studies continue to confirm this, we may be able to use it in conjunction with other treatments, such as chemotherapy, because there may be a synergistic effect. In other words, TM-601's ability to impede cancer growth could allow us to reduce the dose of chemotherapy to achieve a therapeutic effect," said Mamelak, who serves as co-director of the Pituitary Center at Cedars-Sinai.

About 17,000 Americans are diagnosed with gliomas each year. The tumors are extremely aggressive and deadly, with only eight percent of patients surviving two years and three percent surviving five years from time of diagnosis. Even when surgery is performed to remove a glioma, some cancer cells invariably remain behind and proliferate.

"Despite advances in surgical technology, radiation therapy and cancer-killing drugs, length of survival has remained virtually unchanged for patients with gliomas," said Keith L. Black, M.D., director of the Maxine Dunitz Neurosurgical Institute and interim chair of Cedars-Sinai's Department of Neurosurgery. "Only in the recent past have we begun to discover some of the molecular, genetic and immunologic mechanisms that enable these deadly cancer cells to evade or defy our treatments, and we are developing innovative approaches, such as this one, that capitalize on these revelations."

Patients who consented to participate in the Phase I study first underwent tumor-removal surgery. Fourteen to 28 days later, a single, low dose of radioactive iodine (131I) attached to TM-601 was injected through a small tube into the cavity from which the tumor had been removed.

Although TM-601 had been tested in earlier laboratory and animal experiments, it had never been given to humans. Therefore, the primary objective of this study was to document that 131I-TM-601 could be administered to humans safely. In addition, the researchers sought to begin to assess the drug's anti-tumor effect and dosing standards. Six patients agreed to receive additional doses at one of three different levels (.25 mg. of TM-601, .5 mg. of TM-601, and 1 mg. of TM-601, each carrying the same amount of iodine).

"In this first human trial, treatment of patients with recurrent high-grade glioma with a single intracavitary dose of 131I-TM-601 was well tolerated to the maximum dose . Very few adverse side effects occurred during the initial 22-day observation period, suggesting the dosing level of peptide used in this study is safe and well-tolerated in humans," the article states.

While median length of survival for all patients was 27 weeks, two patients, women in their early 40s, had a "complete radiographic response," meaning there was no evidence of residual tumor according to magnetic resonance imaging scans. The patients were still alive beyond 33 and 35 months after surgery, despite the low dose of TM-601 and radiation levels that were below expected therapeutic levels.

Analyses also showed that most of the radioactivity delivered by the drug left the region within 24 hours of administration. That which lingered was "tightly localized to the tumor cavity and surrounding regions, suggesting discrete binding to the tumor." The drug was eliminated primarily through the urine, with radiation doses to the thyroid and other vital organs remaining extremely low and harmless.

Chromosomal Testing Can Determine Brain Tumor Therapy

Sat, 01 Jul 2006 03:39:00 PST

( from http://www.rxpgnews.com ) A trial involving two types of rare, malignant but treatable brain tumors shows that missing portions of two chromosomes can predict which patients will likely do better with therapy. The results, says senior author Walter J. Curran Jr., M.D., professor and chair of radiation oncology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, represents a paradigm shift in treating such tumors, known as gliomas.

Reporting last week in the Journal of Clinical Oncology, Dr. Curran and a team of American and Canadian researchers, in conjunction with the Philadelphia-based Radiation Therapy Oncology Group (RTOG), a federally-supported clinical trials organization, found that among 289 patients with either anaplastic oligodendroglioma or anaplastic oligoastrocytoma receiving either a combination of three chemotherapy drugs with radiation or radiation alone, those whose tumors had deletions in chromosome locations 1p and 19q tended to live nearly two and a half times longer than those patients without the missing chromosome portions. The median survival time of patients with the deletions was greater than seven years, meaning that one-half lived at least that long. For those with tumors lacking such deletions, one-half lived at least 2.8 years.

Leukemias used to be the only cancers where chromosomal deletions were part of the treatment decision-making process, says Dr. Curran, who is also clinical director of the Kimmel Cancer Center at Jefferson. Now, testing for such deletions in tumors should become mandatory for at least these types of gliomas.

In the study, 147 patients received the chemotherapy and radiation, while 142 were given only radiation. These rare, malignant tumors can be effectively treated, though seldom cured with surgery and radiation. One controversy, explains Dr. Curran, was whether or not adding chemotherapy early in the treatment will help individuals live longer. Most thought that chemotherapy would be beneficial.

However, the researchers found little difference in survival after three years between the two groups. While the group who received chemotherapy and radiation lived nearly a year longer without evidence of the cancer growing, nearly two-thirds of those patients experienced significant toxic side effects from the treatment.

Dr. Curran explains that there was some indirect evidence that showed that individuals with these types of tumors who had chromosomal deletions fared better. When the scientists compared the patients who had deletions and those who did not, they found stunning results.

While finding unexpectedly that adding chemotherapy didnt help survival, equally important was the fact that we confirmed in a multicenter trial that the 1p and/or 19q deletion was highly predictive and prognostic of patient outcome, whether the patient received radiation and chemotherapy or radiation alone, Dr. Curran says. Whether the patient had one or both deletions, the survival is much better.

In the same journal issue, a European team showed nearly identical results in a similar trial. Both trials showed such deletions were predictive of survival, Dr. Curran says.

These two studies together have shifted the way we think of anaplastic or grade three gliomas, he says. Up until now weve categorized them based on histologic appearance. We are now categorizing them according to chromosomal deletion status.

Thats actually more predictive than what they look like under the microscope, Dr. Curran says. Those who have no chromosomal deletions have outcomes not all that different than the grade four glioblastomas, a much more deadly brain tumor. Those with both deletions are a totally different group of patients.

Testing for chromosomal deletions should be a mandatory part now of the management of these patients based on these two trials.

There has been a shift in clinical trial design in the last year, he says. Now in patients with gliomas, we are going to apply this to future study design and probably treatment recommendations based on chromosomal deletions. I think more and more centers will begin to use such diagnostic genetics.

Motexafin gadolinium extends cognitive function in patients with brain metastases

Tue, 06 Jun 2006 14:44:00 PST

( from http://www.rxpgnews.com ) The drug Xcytrin®, based on a molecule developed by chemists at The University of Texas at Austin, shows significant promise in prolonging cognitive function in patients with non-small cell lung cancer that has metastasized to the brain.

This result, presented at the annual meeting of the American Society of Clinical Oncology on June 5, supports Pharmacylics, Inc.'s recent decision to file a New Drug Application with the U.S. Food and Drug Administration.

In a Phase 3 trial, Xcytrin was delivered in conjunction with whole brain radiation treatment to patients with non-small cell lung cancer that had spread to the brain. Xcytrin significantly prolonged the time to neurologic progression, which is described as a change in mental status, vision and muscle strength associated with the progression of brain cancers.

"In conjunction with radiation, Xcytrin enhances cancer cell death," said Dr. Jonathan Sessler, professor of chemistry and biochemistry and co-founder of Pharmacyclics (Sunnyvale, Calif., PCYC). "Radiation puts stress on the cells and the drug puts further stress on the cells. Add them together and the cells start to die."

More than 500 patients from North America, France and Australia participated in this Pharmacyclics trial combining Xcytrin injection with whole brain radiation. In North America, patients receiving the treatment experienced neurologic progression 16 months later than patients not receiving the treatment.

Xcytrin (motexafin gadolinium) is based on texaphyrin molecules developed in Sessler's lab. Texaphyrins are large, "Texas-sized" versions of porphyrins, which are highly pigmented molecules responsible for the color of red blood cells. Texaphyrins localize to cancer cells and disrupt cellular metabolism and energy production, weakening or destroying the cells. The molecules are relatively non-toxic to normal cells.

Sessler's texaphyrins were designed to hold heavy metals like gadolinium, commonly used to produce magnetic resonance imaging (MRI) agents. As a consequence, Xcytrin allows tumors to be visualized through MRI. The ability to both detect and treat brain and other cancers using the same agent could prove advantageous in a clinical setting, which Pharmacyclics and its collaborators are studying in the context of ongoing early stage clinical trials. Other trials are now underway to test the potential of Xcytrin to act as a stand-alone chemotherapeutic agent or in combination with other known cancer drugs.

New vaccine to fight glioblastoma multiforme developed

Tue, 02 May 2006 22:40:00 PST

( from http://www.rxpgnews.com ) A vaccine to fight an aggressive form of brain tumour has been developed by US scientists, who say it can delay progression of the cancer.

Scientists say the vaccine increased survival rates by at least 18 months for the 23 patients of glioblastoma multiforme that it was tested on, reported the online edition of BBC News.

One in four brain tumours are glioblastoma multiforme (GBM), the most aggressive form of the primary brain tumours known collectively as gliomas.

These tumours arise from the supporting glial cells of the brain. These growths do not spread throughout the body like other forms of cancer, but cause symptoms by invading the brain.

The developed vaccine, an easy-to-use "off-the-shelf" treatment, could potentially help half of all patients with glioblastoma multiforme (GBM), said Amy Heimberger, assistant professor of neurosurgery at the MD Anderson Cancer Center, Texas.

Trial results showed that the vaccine significantly delays the progression of tumours until the cancer finds a new way to grow. A larger trial of the vaccine, which works by targeting a protein thought to drive the tumour's spread, is now planned.

New mouse model that closely mimics human medulloblastoma

Fri, 28 Apr 2006 01:38:00 PST

( from http://www.rxpgnews.com ) Researchers have created a mouse model that closely mimics human medulloblastoma, the most common type of childhood brain tumor. The new model, which was created by knocking out a key component of the DNA repair machinery, will aid in exploring the genetic roots of this deadly brain cancer.

The researchers, led by Howard Hughes Medical Institute investigator Frederick W. Alt, published their findings the week of April 24, 2006, in the early online edition of the Proceedings of the National Academy of Sciences. Catherine Yan, who is in Alt's laboratory at Children's Hospital Boston, was lead author of the article. Other co-authors were from Brigham & Women's Hospital, CBR Institute of Biomedical Research, Children's Hospital and Dana-Farber Cancer Institute, all of Harvard Medical School.

Although childhood cancers are rare, brain tumors are among the most common. About one out of five childhood brain tumors is medulloblastoma, an aggressive cancer of the cerebellum. Alt and his colleagues produced the mouse model of medulloblastoma by knocking out a gene called XRCC4, which produces a protein that plays an important role in stitching together the ends of broken DNA. These breaks which can occur in all cell types from exposure to radiation, chemicals, or other insults, occur specifically in the immune system when genes are snipped and rearranged to produce a vast array of antibodies. The abnormal swapping of chromosomal regions that ensues when such repair goes awry--known as chromosomal translocations--is sometimes harmless, but can contribute to cancer and other diseases.

In earlier studies, Alt and his colleagues discovered that XRCC4 is a component of nonhomologous end-joining, a process that is essential for the repair of chromosome breaks. They found that knocking out this gene in mice led to widespread death of newly generated neurons and death late in embryonic development. The researchers then combined these experiments with the elimination of a gene for a sentinel protein called p53, which triggers the death of malfunctioning cells. With both p53 and XRCC4 missing, neurons survive and the mice live into early adulthood, but then die of lymphomas caused by translocations of antibody genes. The researchers noted that by this time, the mice were also beginning to develop medulloblastomas.

After they made that observation, Alt's team wanted to zero in on the possible role of XRCC4 deficiency in medulloblastomas. While their earlier studies involved knocking out the XRCC4 gene throughout the animals' bodies, now âthe major goal was to eliminate this protein only in the developing nervous system, so we could specifically determine whether there was a role for nonhomologous end-joining in suppressing cancers of cells besides those of the immune system,â he said. âWe also wanted to know whether getting rid of both XRCC4 and p53 in the nervous system would predispose the animals to neuronal tumors, and whether or not those tumors would also be associated with particular chromosomal translocations.â

So Yan and her colleagues engineered two strains of mice in which XRCC4 was knocked out only in neural progenitor cells in the developing nervous system. One strain had only the XRCC4 knockout, and the other also had a deficiency in both XRCC4 and p53. These mice appeared to develop normally without XRCC4, they found. But every mouse lacking both XRCC4 and p53 died very early of medulloblastomas. Furthermore, âthose tumors strongly resembled human medulloblastomas,â said Alt.

Analyzing the tumors for genetic abnormalities, Alt and his colleagues found that specific genes were frequently altered in association with recurrent chromosomal translocations--and that affected genes often were those activated or inactivated in human medulloblastomas. Thus, the tumors often showed amplifications of two genes called N-myc and Cyclin D2, which are characteristic of many human neural tumors, including medulloblastomas. The animals also showed the loss of one copy of a gene called patched, which is also characteristic of some human medulloblastomas.

âOnly in our wildest dreams had we hoped to see these kinds of recurrent translocations,â said Alt. âIt's quite exciting to us that we'll be able to explore mechanistically why they happen when the basic process of end-joining is compromised.â

Other mouse models of medulloblastoma have been created by knocking out patched or other individual genes that have been implicated in the development of medulloblastoma. However, said Alt, âwhat we did was different. We created an environment in which end-joining was defective and let the biology of the cell sort out the consequences. And while in most other models not every mouse develops medulloblastomas, in our case every animal very reproducibly develops these tumors at a very young age. It's really quite intriguing, too, how this general genomic instability very specifically leads to the selection of tumor cells that have deregulated particular genes such as N-myc, patched and Cyclin D2.â

According to Alt, the new mouse model will prove valuable in understanding why N-myc is so frequently amplified in human tumors, including neuroblastomas and medulloblastomas, and the consequences of that amplification. The model also will enable the researchers to better explore causes of the chromosomal translocations, deletions, and amplifications in neuronal cells.

The mouse model should also be useful in testing potential treatments for medulloblastoma. Alt said that other laboratories have consulted them on the possibility of using the model for drug testing. âThis model could be very useful for such a purpose because every mouse gets tumors with an early onset and the tumors show activation or inactivation of a set of genes that is implicated in human tumors,â he said. âSo, if one wants to test therapies that interfere with pathways involved in human tumors, this should be a good model.â

Immune response protects against brain tumor development

Mon, 03 Apr 2006 07:02:00 PST

( from http://www.rxpgnews.com ) In their quest to determine whether immune system surveillance guards against brain tumor development, researchers at The University of Texas M. D. Anderson Cancer Center have found that allergies and asthma that stimulate inflammation may be protective, but use of antihistamines to control the inflammation could eliminate that protection.

In this study, reported at the annual meeting of the American Association for Cancer Research (AACR), the researchers also associated chicken pox infection with a significantly reduced risk of developing brain tumors.

The researchers say the findings suggest that a small amount of inflammation in the brain may rev up the immune system enough to protect against brain tumor development. But they stress that no one should give up antihistamines or shun use of a chicken pox vaccine because of this study.

"Brain tumors are exceedingly rare, and many, many people use antihistamines, so we certainly are not suggesting a direct connection between the two, or between chicken pox and tumors," says the study's lead author, Melissa Bondy, Ph.D., a professor in the Department of Epidemiology. "What this study may do is help us begin to understand if the immune system plays a role in development of different kinds of brain tumors."

"Our long-term goal is to look at genes that may be increasing or reducing risk of developing these tumors, and then to assess whether some individuals might be genetically susceptible," says Michael E. Scheurer, Ph.D., a postdoctoral fellow in the Department of Epidemiology. As the study's first author, Scheurer will present the findings at the conference and also in a media briefing Tuesday, April 4 at 1 p.m.

In this study, Scheurer and Bondy combined data from their large Harris County, Texas, epidemiological study of brain tumor patients with information collected on patients in the San Francisco area by researchers at the University of California, San Francisco. Together, they compared medical histories of 830 brain tumor patients matched to a control group of 831 individuals. Within the patient group were 339 cases of glioblastoma (GBM), the most aggressive and lethal type of brain tumor, as well as 117 cases of midgrade anaplastic astrocytoma (AA) and 154 cases of low-grade gliomas (LGG).

The research team considered recent studies that suggest immune system activity in the brain may protect against brain tumor development and that people who have allergies or asthma have a reduced risk of developing a glioma.

"It could be that allergies and asthma produce enough inflammation in the brain to keep immune system cells active, and that this surveillance works to eliminate cancer beginning to develop in the brain," Scheurer says. "So we wondered whether use of antihistamines that counter that inflammation eliminates the protective effect."

They found that, indeed, a history of allergies and asthma was significantly protective for the three different kinds of brain tumors examined in the study. Individuals with the disorders had a 35 percent reduced risk of developing GBM, a 51 percent reduced risk of AA, and a 36 percent reduced risk of LGG.

They also found that participants who used antihistamines were more likely to develop brain tumors. Participants who used antihistamines had three times the risk of developing an AA tumor and two times the risk of developing LGG, compared to those who did not use antihistamines. The risk of developing a GBM was also increased by 26 percent, but that was not statistically significant, the researchers say.

"This suggests that among people who are susceptible, those who have allergies and don't do anything about it may be protected to some degree against brain tumors," Bondy says. "But those who use antihistamines could decrease that protection and increase their risk. The real question is if there are particular gene variants that would make a person susceptible."

The researchers also asked participants about their history of chicken pox. A latent infection is known to promote low level inflammation in the brain, which could also provide an immune response that protects against tumor development. They found that a history of chicken pox significantly reduced the risk of developing AA tumors. The risk of developing the other two kinds of tumors studied was also reduced (40 percent for GMB and 22 percent for LGG), but not significantly so.

Finally, the researchers looked at use of anti-inflammatory (Cox-2 inhibitors) drugs among study participants and found a significant reduction (31 percent) in development of GBM among those who used them.

"There are three pathways that lead to inflammation in the brain, and reducing one with a Cox-2 inhibitor may be beneficial," Bondy says.

"These are all interesting signals that may give us a clue as to the role of inflammation and development of different kinds of brain tumors," Scheurer says. "We will need much more epidemiological and genetic data to make any firm conclusions and are collaborating with other institutions to pull that information together."

Long mobile use could cause brain tumours - New Study

Mon, 03 Apr 2006 07:01:00 PST

( from http://www.rxpgnews.com ) Using a cell phone for long periods could lead to malignant brain tumours, says a new study contradicting earlier findings which found no such link.

Earlier studies did not find evidences that radiation from cell phones was linked with elevated brain tumour risk although the damaging effect of cell phone use has been suspected for long.

Those who used a cell phone for 2,000 hours or for one hour a day over a period of more than 10 years increase their risk of a malignant brain tumour on the side of the head, according to a new study published in the International Archives of Occupational and Environmental Health.

Researchers led by Kjell Mild, of the Swedish National Institute for Working Life, compared cell phone use of 2,200 patients with malignant tumours and an equal number of healthy control cases.

Among the tumour patients (aged 20 to 80), 905 had a malignant brain tumour and one third of them were heavy users of cell phones, it said.

"Of these 905 cases, 85 were high users of mobile phones," the study authors said.

Children should avoid using cell phones whenever possible because they are most vulnerable to tumour risk than adults, the study warned.

Donepezil helps cognitive function in brain tumor patients after radiation

Sun, 19 Mar 2006 20:50:00 PST

( from http://www.rxpgnews.com ) A drug that is marketed to treat Alzheimer's disease also improves cognitive function, mood and quality of life in brain tumor patients following radiation therapy, according to a research team at Wake Forest University Baptist Medical Center.

After the patients were treated for six months with donepezil (trade name: Aricept), there was a significant improvement in their symptoms, the researchers reported in the March 17 issue of the Journal of Clinical Oncology.

"Each year more than 15,000 Americans are diagnosed with a primary brain tumors, and as many as 200,000 with metastatic brain tumors, nearly all of whom receive radiation therapy," said Edward G. Shaw, M.D. "For survivors of brain tumor radiation, symptoms of short-term memory loss and mood changes similar to those seen in Alzheimer's disease, as well as fatigue, frequently occur, leading to a poor quality of life."

Donepezil, part of a class of drugs called acetylcholinesterase (AChE) inhibitors, "has demonstrated efficacy in mild to severe Alzheimer's disease and vascular dementia," said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine and senior author on the paper. It is approved by the U.S. Food and Drug Administration for that purpose.

"The results of this initial study encourage continued investigation of donepezil and other AChE inhibitors," Rapp said.

The research team is planning a clinical trial in which treatment of brain tumor patients with donepezil will be compared to an inert placebo, and neither the doctor nor the patient will know which pill they received until the study is completed.

"To our knowledge, this is the first study of an AChE inhibitor or any other drug administered to long-term survivors of partial or whole brain radiation therapy in an attempt to reduce the symptoms associated with a brain tumor and its treatments," said Shaw, professor and chairman of the Department of Radiation Oncology and a co-author.

"The pretreatment assessment of thinking, memory, mood and energy level revealed symptoms that clearly affected quality of life," Shaw said.

The researchers decided to try donepezil after observing that radiation-induced brain injury resembles Alzheimer's disease and other forms of dementia not only in the clinical symptoms but also in what is seen with brain imaging, particularly with magnetic resonance imaging (MRI) and positron emission tomography (PET).

The team hypothesized that radiation therapy for brain tumors resulted in injury to neurons that in turn caused a deficiency of a brain chemical called acetylcholine. They thought use of an AChE inhibitor such as donepezil might increase the acetylcholine level in the brain, decrease cognitive symptoms and improve mood and quality of life. Their study indicated it did.

"Additional research is needed to further evaluate donepezil and other AChE inhibitors in this population." Rapp said.

Infections could trigger some adult brain tumours

Tue, 24 Jan 2006 15:54:00 PST

( from http://www.rxpgnews.com ) Infections could play a key role in triggering certain types of adult brain cancer, according to results from a new statistical analysis of the disease.

The international study, led by Dr Richard McNally at the University of Newcastle upon Tyne, was funded by Cancer Research UK, the Dutch Cancer Society, and the Christie Hospital Research Endowment Fund.

The British and Dutch team analysed a database of adult brain tumours diagnosed in patients from the North Brabant province of the Netherlands between 1983 and 2001. They found clusters of cases of glioma tumours, which make up about half of all brain tumours, at different time intervals in different geographical locations.

This 'space-time clustering' of cases is a pattern typical of diseases caused by infections, adding weight to the theory that outbreaks of viruses are a potential contributory cause of brain tumours. Diseases caused by more constant environmental factors, such as pollution, produce clusters of cases in one place over a much longer time period.

However, the research team stresses it is too early to say exactly which infections could be the cause, and say that more research is needed to pinpoint what they are.

The findings, published in the European Journal of Cancer, may potentially be a step towards developing better preventative measures for cancer and may also result in better treatment.

Dr Richard McNally, of Newcastle University's School of Clinical Medical Sciences (Child Health), said: "Very little is known about the cause of brain tumours and we think our research brings us closer to understanding more about this disease.

"We only found clustering of cases in the East of the province we investigated, and we think it could be something to do with the way infections spread in less densely populated areas."

However, the researchers stress that people cannot 'catch cancer'. Infections are only likely to trigger cancer in a very small number of individuals who are already genetically susceptible to the disease.

The team looked at data from the Eindhoven Cancer Registry. They analysed results for the East and West of the 5000 square-kilometre province separately. They found an irregular pattern where many cases occurred at the same time in men and women over 15-years old in the East but not in the West. Around seven per cent more cases of brain tumours were observed to occur in 'clusters' than would be expected by chance.

This is the first study to carry out this sophisticated form of statistical analysis known as 'clustering' in brain tumours in adults.

The results of this work are consistent with earlier research led by Dr McNally into childhood cancer in North West England. This discovered patterns in the diagnosis of two types of cancer - leukaemia and brain tumours - in that they tended to occur together at similar times and geographical locations.

Dr McNally, who also works with Newcastle University's School of Population and Health Sciences, added: "Future research should try to identify specific infections which could potentially be a trigger. If these are found, it could lead to future preventative measures."

Professor John Toy, Cancer Research UK's medical director, said: "Brain cancer is rare, accounting for less than two per cent of all new adult cancers diagnosed in the UK each year. These findings suggest a possible link between infection and this type of the disease but by no means provide proof."

Mobiles not linked to increased risk of brain tumours

Sat, 21 Jan 2006 16:21:00 PST

( from http://www.rxpgnews.com ) Mobile phones are not associated with an increased risk of the most common type of brain tumour, finds the first UK study of the relationship between mobile phone use and risk of glioma. The results are published online by the BMJ.

The four year study by the Universities of Leeds, Nottingham and Manchester and the Institute of Cancer Research, London found those who had regularly used a mobile phone were not at a greater overall risk of developing this type of tumour.

There was no relationship for risk of glioma and time since first use of a mobile phone, lifetime years of use and cumulative number of calls and hours of use. Risk was not associated with phone use in rural areas which was found to be associated with an increased risk in an earlier Swedish study.

A significantly increased risk was found for tumours which developed on the same side of the head as the phone was reported to have been held but this was mirrored by a decrease in the risk on the opposite side of the head making it difficult to interpret as a real effect.

This finding may be due to people with glioma brain tumours linking mobile phone use to the side of the tumour and therefore over reporting the use of a phone on the same side as their tumour. This results in under reporting use on the opposite side of the head, say the authors.

Mobile phones have been available in the UK since 1985, but widespread use did not begin until the late 1990s making the number of long term users (over 10 years) quite small. This study had limited numbers for estimating the risk of using a phone over a long period.

Early mobile phones were designed to use analogue signals and emitted higher power than current digital phones but the study showed no increased risk of glioma brain tumours with the use of analogue phones.

Notes to Editors: There are over 4,000 new cases of brain tumours per year of which glioma is the most common type. Early symptoms include headaches and feelings of nausea. The causes of these tumours are currently unknown.

The study was conducted between 1 December 2000 and 29 February 2004 and included people living in the Thames region, southern Scotland, Trent, the West Midlands and West Yorkshire.

966 people with glioma brain tumours (cases) and 1716 healthy volunteers (controls) were interviewed about their previous mobile phone use history including how long they had used mobile phones, the number and duration of the calls they made and what make and model of phone they had used.

No link between mobile phones and glioma

Fri, 20 Jan 2006 15:14:00 PST

( from http://www.rxpgnews.com ) Mobile phones are not associated with an increased risk of the most common type of brain tumour, finds the first UK study of the relationship between mobile phone use and risk of glioma.

The four year study by the Universities of Leeds, Nottingham and Manchester and the Institute of Cancer Research, London found those who had regularly used a mobile phone were not at a greater overall risk of developing this type of tumour.

There are over 4,000 new cases of brain tumours per year of which glioma is the most common type. Early symptoms include headaches and feelings of nausea. The causes of these tumours are currently unknown.

The study was conducted between 1 December 2000 and 29 February 2004 and included people living in the Thames region, southern Scotland, Trent, the West Midlands and West Yorkshire.

There was no relationship for risk of glioma and time since first use of a mobile phone, lifetime years of use and cumulative number of calls and hours of use. Risk was not associated with phone use in rural areas which was found to be associated with an increased risk in an earlier Swedish study.

A significantly increased risk was found for tumours which developed on the same side of the head as the phone was reported to have been held but this was mirrored by a decrease in the risk on the opposite side of the head making it difficult to interpret as a real effect.

Mobile phones have been available in the UK since 1985, but widespread use did not begin until the late 1990s making the number of long term users (over 10 years) quite small. This study had limited numbers for estimating the risk of using a phone over a long period.

Early mobile phones were designed to use analogue signals and emitted higher power than current digital phones but the study showed no increased risk of glioma brain tumours with the use of analogue phones.

966 people with glioma brain tumours (cases) and 1716 healthy volunteers (controls) were interviewed about their previous mobile phone use history including how long they had used mobile phones, the number and duration of the calls they made and what make and model of phone they had used.

This finding may be due to people with glioma brain tumours linking mobile phone use to the side of the tumour and therefore over reporting the use of a phone on the same side as their tumour. This results in under reporting use on the opposite side of the head, say the authors.

Discovery could change the way doctors treat glioblastomas

Fri, 11 Nov 2005 00:46:00 PST

( from http://www.rxpgnews.com ) Researchers at UCLA's Jonsson Cancer have identified key characteristics in certain deadly brain tumors that make them 51 times more likely to respond to a specific class of drugs than tumors in which the molecular signature is absent.

The discovery of the telltale molecular signature the expression of a mutant protein and the presence of a tumor suppressor protein called PTEN will allow researchers to identify patients who are likely to respond to the drug treatment before they undergo therapies that are not likely to work, said Dr. Paul Mischel, a UCLA associate professor of pathology and laboratory medicine and a Jonsson Cancer Center researcher.

Mischel and his colleagues write in an article in the Nov. 10 issue of the New England Journal of Medicine that the discovery could change the way doctors treat glioblastomas, the most common type of malignant brain tumor and one of the those lethal forms of cancer.

"In a biologically aggressive disease like glioblastoma, it's vital to be able to stratify patients up front so we can treat them with drugs that they are more likely to respond to," Mischel said. "This will help prevent patients from having therapies that are much more toxic and less beneficial. With the short survival times associated with glioblastoma, that is critical."

Between 8,000 and 10,000 new cases of glioblastoma will be diagnosed in Americans this year. Average survival is less than a year, according to the American Cancer Society. Although treatment may prolong life, most malignant brain tumors are not curable, making the search for better treatments even more urgent, Mischel said.

A protein called epidermal growth factor receptor (EGFR) is commonly amplified in glioblastoma, making it a prime focus for therapies. Drugs such as Tarceva and Iressa target EGFR, blocking the cell signals that drive amplification of the protein and speed cancer growth. A subset of glioblastoma patients responded to Tarceva and Iressa, but it was not clear what characteristics made them respond to these drugs. There had to be critical molecular factors that determined response, Mischel said.

He and his team set out to find the molecular determinants that indicated which patients would respond best to EGFR blockers. Previous UCLA research in brain and other cancers suggested that the key might be the interaction of the PTEN protein and a mutant protein called EGFRvIII. About half of patients with amplified EGFR also have this mutant protein.

The UCLA team and their collaborators studied a subset of 26 glioblastoma patients who either responded very well or very poorly to EGFR-blocking drugs and developed a way to test their brain tumor tissue for the presence of both the mutant and PTEN proteins. Mischel's team found that patients with both genetic variations were 51 times more likely to respond to EGFR blockers. They also lived five times longer after initiating therapy than those without the variation, surviving 253 days versus 50 days.

To confirm their promising work, Mischel and his team obtained tissue samples from 33 brain cancer patients treated at another facility without knowing who the responders were. They were able to replicate their results independently, confirming that those with both genetic variations were more likely to respond to EGFR-blocking drugs.

The study shows that glioblastoma patients can respond to targeted agents, and suggests that patients likely to benefit from treatment can be identified by molecular testing. The study also raised the possibility that patients whose tumors lack the genetic variations in the molecular signature could possibly be treated with drugs to make them more sensitive to EGFR blockers.

Of the 8,000 to 10,000 glioblastoma patients diagnosed each year, about 10 percent to 20 percent have the combination of the mutant and PTEN proteins, Mischel said. The next step is a prospective study determining the molecular signature of patients' tumors and directing those with the right protein combination to EGFR-blocking therapies. Mischel's team also is working to uncover the molecular signatures in the tumors of non-responders so they can determine what therapies might be most effective for them.

"This is a much more hopeful period now in cancer research," Mischel said. "Genomic and proteomic technologies are helping us begin to understand the underlying molecular features of disease, and new drugs are making it possible to safely and specifically target pathways that are altered in cancer cells. This was impossible five years ago. Glioblastoma is still a difficult disease, but the idea that it may be possible to induce long-term disease suppression gives us reason for hope."

The study, Mischel said, also may have important implications in other cancers.

"Many cancers have a similar combination of a mutant cancer-causing protein and either the expression or loss of the PTEN protein," Mischel said. "The interactions of the two may be important in determining response to targeted agents."

Glioblastoma Gene Variations Can Predict Treatment Response

Fri, 11 Nov 2005 00:20:00 PST

( from http://www.rxpgnews.com ) Screening glioblastoma brain tumors for two gene variations can reliably predict which tumors will respond to a specific class of drugs, a new study shows. The findings may lead to improved treatment for this devastating disease. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), and appears in the November 10, 2005, issue of the New England Journal of Medicine.*

Glioblastomas are the most common malignant brain tumors in adults, and they are notoriously difficult to treat successfully. "The survival with glioblastoma is usually a year on average, and that hasn't improved in a while, so this is a very serious and challenging disease," says Paul Mischel, M.D., of the David Geffen School of Medicine and Jonsson Comprehensive Cancer Center at the University of California , Los Angeles (UCLA), who led the study. While drugs are available to help treat glioblastoma, they often have minimal effect, and doctors usually have time to try only one or two treatments before the disease causes severe impairment. Glioblastomas feature many genetic variations that affect their response to different treatments. Researchers are trying to identify these genetic factors and to tease apart how they affect the disease in order to determine which patients are the most likely to benefit from specific drugs.

In the new study, Dr. Mischel and his colleagues performed genetic analysis on tissue from recurrent malignant glioblastoma patients, 26 of whom responded either very well or very poorly to the drugs erlotinib (Tarceva®) and gefitinib (Iressa®). These two drugs belong to a class called EGFR (epidermal growth factor receptor) kinase inhibitors, and both are currently approved by the by the U.S. Food and Drug Administration (FDA) to treat advanced lung cancer that has not responded to other treatments.

Based on results from other studies, the researchers hypothesized that variations in several different genes might play a role in the tumor's response to EGFR inhibitors. They looked for mutations in genes called EGFR and HER2/neu, and they analyzed the activity of EGFR, an EGFR variant called EGFRvIII, and a gene called PTEN. Many tumors not just brain tumors have mutations or abnormal activity of one or more of these genes, which help to control cell growth and other functions.

Glioblastomas that produced both EGFRvIII and PTEN were 51 times more likely to shrink when treated with EGFR inhibitors than tumors without this combination of proteins, the researchers found. Patients whose tumors expressed these proteins and who received an EGFR inhibitor went almost 5 times longer on average before their tumors progressed (243 days vs. 50 days) than those whose tumors did not express both of the proteins. In contrast, EGFR and HER2/neu activity had no effect on how tumors responded to these drugs. Similar results were found in tissues from another group of 33 glioblastoma patients who had taken part in a clinical trial of erlotinib at the University of California , San Francisco .

The findings suggest that both EGFRvIII and PTEN proteins are important for tumors to be susceptible to EGFR inhibitors, Dr. Mischel says. Their data further suggest that EGFRvIII may act to sensitize glioblastoma cells, while PTEN loss may act as a resistance factor. The researchers tested their results in several different cell models and repeatedly found that expression of these two proteins made the cells sensitive to EGFR inhibitors and that PTEN loss promoted resistance in those models.

The study shows that genetic analysis of glioblastomas can predict the tumors' sensitivity to specific drugs. Adjusting treatment based on each tumor's genetic activity could significantly prolong life for a subset of glioblastoma patients, Dr. Mischel says. It also may prevent patients from undergoing unnecessary and expensive treatments, and it could allow some people to be treated with the most effective therapy immediately, before the tumors can grow and develop new mutations that make them more difficult to treat.

Kinases are enzymes that play key roles in cell proliferation, metabolism, and other functions, and they are often overactive in cancer cells. Because cancer cells may become dependent on the persistent signals created by altered kinases in a way in which non-cancerous cells do not, kinase inhibitors such as EGFR inhibitors can often target cancer cells without seriously affecting the rest of the body. Therefore they cause fewer side effects than most other cancer drugs. The drug imatinib (Gleevec®), which is FDA-approved to treat chronic myeloid leukemia, is one of the early success stories for this kind of treatment.

The study also reveals important information about how glioblastomas and other tumors develop, Dr. Mischel says. Knowing that EGFRvIII and PTEN play critical roles in tumor response to treatment could lead to new combination therapies that target both proteins. Such therapies might also be beneficial for other types of cancer.

Screening for these factors also might allow researchers to better determine a treatment's effects in clinical trials, Dr. Mischel adds. Traditional clinical trials that do not take into account each tumor's genetic makeup often fail to show enough of an effect to warrant FDA approval for a drug because only a subset of patients respond well to the treatment.

The researchers are now planning prospective clinical trials to determine whether selecting treatment based on each tumor's genetic activity can lead to better patient survival. They also plan to continue looking for other tumor susceptibility factors, to develop new treatments that target those factors, and to try to learn how some patients become resistant to treatment. Researchers also need to develop their genetic screening techniques into a diagnostic test so that it can be available to all people with glioblastoma, Dr. Mischel says.

Evidence-based Review on Radiation for Brain Tumors

Sun, 11 Sep 2005 21:41:00 PST

( from http://www.rxpgnews.com ) The American Society for Therapeutic Radiology and Oncology gathered a panel of experts to compile and analyze existing studies on the use of radiosurgery, a specialized type of external beam radiation therapy that pinpoints high doses of radiation to treat brain tumors. The panel has developed evidence-based reviews that consolidate the information available and identify questions to be answered in future research. The two new reviews are published in the September 1, 2005 issue of the International Journal of Radiation Oncology*Biology*Physics, the official journal of ASTRO.

Evidence-based medicine is the conscientious, explicit and judicious use of current evidence in making decisions about the care of patients. The papers are generated by a panel of recognized experts in the field and summarize information ranging from a single randomized, controlled trial to descriptive studies based on clinical experience and the opinions of respected authorities. The review takes current medical literature on a certain topic, in this case brain tumors, and identifies questions for further research.

In this instance, the panel of doctors reviewed all available information on radiosurgery for both brain metastases and malignant glioma from the published literature and scientific meetings of several cancer organizations, including ASTRO, the American Society of Clinical Oncology and the European Society for Therapeutic Radiology and Oncology. After carefully assessing the literature, the panel created a summary of the evidence in the use of radiosurgery for brain metastases and one for malignant glioma; each provide centrally located treatment information for doctors and chart a course for further research.

It is not known whether or not the research we recommend will be superior or equivalent to the current treatment, said May N. Tsao, M.D., a radiation oncologist at Sunnybrook Regional Cancer Center in Toronto, Ontario, Canada and lead author of the malignant glioma review. However, we owe it to the patients suffering from brain tumors to find out.

Evidence-based reviews are living documents that reflect the best practice for a disease site at a particular time, said Minesh P. Meta, M.D., a radiation oncologist at University of Wisconsin Medical School in Madison, Wis. and lead author of the review on brain metastases. They help us find gaps in research and provide us with a road map of where future research needs to be targeted.

P-gp system let JV-1-36 pass into the brain to treat malignant glioblastomas

Tue, 23 Aug 2005 19:56:00 PST

( from http://www.rxpgnews.com ) A compound that kills cancer can sneak past the blood brain barrier, which protects the brain from foreign substances, to do its work in fighting a particularly invasive brain cancer, according to a new Saint Louis University animal study published in the Proceedings of the National Academy of Sciences Online Early Edition the week of Aug. 22.

"The bottom line is, if you can get drugs into the brain, you can cure brain cancer," says William A. Banks, M.D., professor of geriatrics in the department of internal medicine and professor of pharmacological and physiological science at Saint Louis University School of Medicine and a member of the research team.

The compound JV-1-36 is an antagonist of the hypothalamic growth hormone- releasing hormone, which has been found to cause cancerous tumors, such as malignant glioblastomas, to grow. The main known purposes of the hypothalamic growth hormone-releasing hormone usually are to trigger the hormone that makes children grow and affect how glucose is used in adults.

Researchers found that the P-gp system, an extra guardian located at the blood brain barrier that usually keeps anticancer drugs out of the brain, intercepted some of the JV-1-36 that was injected into mice but let much of it pass into the brain to treat cancer.

"The blood brain barrier is set up to very carefully patrol what it lets into the brain and what it keeps out. It makes these decisions based on the physicochemical properties," says Dr. Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

"Most of our drugs that fight cancers are toxic to cancer cells and to other cells, too. That's why the blood brain barrier locks them out of the brain."

The research was done in collaboration with investigators at Tulane University School of Medicine in New Orleans, including Nobel Laureate Andrew V. Schally, Ph.D.

Dr. Banks said the findings are promising because they show a way to get drugs into the brain to treat cancer.

"There are times when there's a big difference between an animal model and the human condition. In terms of getting drugs across the blood brain barrier to fight cancer, there's not such a big difference. There's pretty much the same rules in any blood brain barrier be it in a mouse or human."

Laura Jaeger, the lead author of the study and a doctoral student in the department of pharmacological and physiological science at Saint Louis University, calls the findings "very positive and a good first step."

Combined gene therapy can eliminate glioblastoma multiforme

Mon, 15 Aug 2005 17:44:00 PST

( from http://www.rxpgnews.com ) Despite aggressive treatment, glioblastoma multiforme (GBM) the most common and deadly of brain cancers usually claims the lives of its victims within six to 12 months of diagnosis. Because GBM is so aggressive, the disease has been the target of a number of laboratory and clinical studies investigating the effectiveness of gene therapy to deliver novel therapies to the brain. In laboratory studies, this type of gene therapy has proved almost completely effective. But in clinical trials, it has had limited effectiveness.

To overcome these limitations, researchers at Cedars-Sinai Medical Center developed a large brain tumor model in laboratory rats that would more accurately predict the outcome of gene therapies in patients. In addition, they tested a genetically engineered virus to deliver two proteins directly to the brain. Their findings, reported in the August 15th issue of the journal Cancer Research, show that the majority of rats bearing large tumors were still alive six months after combined treatment with two proteins: RAdTK, a protein that kills cancer cells, and RAdFlt3L, which stimulates immune or dendritic cells in the brain.

"Our study shows that GBM tumors were completely eliminated in lab rats, likely because the two proteins increase the production of fully mature immune cells within the brain," said Maria Castro, Ph.D., co-director of the Gene Therapeutics Research Institute at Cedars-Sinai Medical Center and the senior author of the study. "This suggests that combined RAdFlt3L and RAdTK gene therapy may ultimately provide an effective treatment for patients undergoing clinical trials with GBM."

GBM tumors derive from brain astrocytes, a cell that normally supports and nurtures the brain's neurons. GBM grows quickly, often becoming very large before any symptoms are experienced. Once GBM is diagnosed, conventional treatment begins with surgery to remove as much of the tumor as possible and is then followed with radiation and/or chemotherapy to slow progression of the disease. But despite aggressive treatment, the tumors recur and patients usually die within a year's time.

To find another way to more effectively treat GBM, scientists have begun investigating the use of gene therapy to deliver novel therapeutic agents directly to the brain. Typically, these studies have tested the use of the suicide gene from the herpes simplex virus to develop a gene therapy approach that kills cancer cells in the presence of the antiviral drug gancyclovir. In laboratory studies, this type of gene therapy has proved almost 100 percent effective. But in clinical trials, it has had limited effectiveness, suggesting that the tumor mass is too large for the gene to effect long-term.

"Because we haven't seen the same positive results with gene therapy in clinical trials that we've seen treating GBM in laboratory rats, we realized that we needed to design a better model that more closely mimicked these tumors in patients," Castro said. "We also wanted to test whether a combined gene therapy strategy using proteins known to kill cancer cells or promote an immune response would work to eliminate these larger tumors in the rats."

Gene therapy is an experimental treatment that uses genetically engineered viruses to transport genes and/or proteins into cells. Just like a viral infection, the viruses work by tricking cells into accepting them as part of their own genetic coding. To make them safe, scientists remove the genetic viral genes that cause infection and engineer them so that they stop reproducing after they have delivered the therapeutic genes.

In this study, the researchers first developed a large GBM tumor model and implanted them in rats, allowing the tumor to grow for 10 days, when they were at their largest. Secondly, the investigators tested the effectiveness of various gene therapies used in combination or individually to see whether they would shrink or eliminate tumors.

To determine whether the size of the tumor significantly affected survival, the researches implanted both large and smaller GBM tumors in rats. The investigators then treated rats bearing GBM tumors with single or combined gene therapies (RAdTK and/or RAdFlt3l), or a saline placebo, as a control. They found that RAdTK treatment was 100 percent effective when delivered into small tumors, but only 20 percent effective when injected into large tumors. RAdFlt3L, on the other hand, was 60 percent effective if delivered into small tumors, but failed completely if injected into the large tumors. But when both RAdTK and RAdFlt3l were given in combination, the investigators found 70 percent of rats were still alive after six months of treatment and that the large GBM tumors had completely disappeared or shrank significantly.

"Just as with patients, our results emphasize that tumor size at the time of treatment is critical to predict clinical outcome," said Pedro Lowenstein, M.D., Ph.D., director of the Gene Therapeutic Research Institute at Cedars-Sinai. "Our model reproduces more closely the human disease condition where tumor size at the time of treatment determines how well the patient will respond to therapies."

"Our results show for the first time, that we could elicit a potent and stable anti-tumor immune response in the brains of rats bearing large GBM tumors," Castro said. "In these pre-clinical studies, combined gene therapy treatment with RAdTK and RAdFlt3L dramatically increased survival, without adverse immune reactions in the brain."

Vaccine to target resistance-related antigen in Brain tumours

Tue, 14 Jun 2005 06:24:00 PST

( from http://www.rxpgnews.com ) In the August issue of the journal Oncogene, researchers at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute describe a molecular mechanism that appears to make malignant brain tumors more vulnerable to chemotherapy after they have been treated with the dendritic cell vaccine.

This finding builds on several studies recently published by the research team. In 2003, they reported that a protein fragment previously found in melanomas also was detected in highly aggressive brain tumors called glioblastoma multiforme (GBM). The immune system recognizes the peptide, Tyrosinase-Related Protein (TRP)-2, as a foreign invader, making it a significant target for immunotherapy.

"Our findings suggest that TRP-2 could be a powerful molecule linking chemotherapy and immunotherapy," said Keith L. Black, M.D, one of the paper's authors, director of the Maxine Dunitz Neurosurgical Institute and director of the medical center's Division of Neurosurgery and Comprehensive Brain Tumor Program.

"Based on our results, it appears that we can improve chemotherapy sensitivity by targeting TRP-2 and possibly other drug-resistant related tumor antigens. This may be a significant step in the fight against brain tumors and other malignant cancers because even as we have been able to develop very powerful and targeted chemicals, tumors have often been able to outmaneuver them," said Black.

In 2004, the researchers documented that the combination of immunotherapy and chemotherapy significantly slowed tumor progression and extended survival of patients suffering from these deadly tumors. The two therapies together were able to accomplish results that neither could achieve by itself. The average length of survival was extended to about 26 months, compared to 18 months for patients who received vaccine alone and 16 months for those undergoing chemotherapy alone.

In a number of laboratory and clinical trials, dendritic cell immunotherapy had succeeded in eliciting a powerful immune response against brain tumor cells, but significant improvements in length of survival had not been realized. One theory is that the rate at which tumor cells die is too slow to keep pace with the rapid growth and mutation of tumors in the body. Similarly, chemotherapy directed against GBM has had very little effect. Even new agents specifically designed to attack the DNA of tumor cells and prevent their replication fail or became impotent as the tumor cells developed drug resistance.

Taking into account recent articles identifying TRP-2 as a contributing factor in the ability of tumor cells to mutate and resist a variety of therapeutic drugs, the Cedars-Sinai team now offers an explanation for the relative effectiveness of this two-wave, vaccine-chemotherapy assault. The first attack comes from the dendritic cell vaccine that is specially formulated to search and destroy tumor cells that contain TRP-2. It clearly launches "cytotoxic T lymphocytes," tumor cell-killing immune cells that diminish or deplete the number of TRP-2-containing tumor cells. Other GBM cells survive, however, and continue to proliferate. But because they lack TRP-2 and therefore the ability to develop drug resistance, they are vulnerable in the follow-up assault of chemicals targeting their DNA.

John S. Yu, M.D., senior author of the paper and co-director of the Comprehensive Brain Tumor Program, said lab results confirmed a strong immune response to TRP-2 in patients' blood cells after vaccination, and cells removed from tumors after vaccination had significantly lower TRP-2 expression than did those removed earlier. Furthermore, the post-vaccine tumor cells were much more sensitive to anti-tumor drugs.

"It is important to note also that four patients in our study that demonstrated a response to TRP-2, after tumor recurrence, responded to chemotherapy with what oncologists call complete responses, which means the tumors were no longer visible on MRI," he added. "This was a small initial study and it will be very interesting to see if similar results will be repeated in larger numbers." Dendritic cell vaccination, pioneered at Cedars-Sinai in the treatment of GBM, introduces foreign proteins from surgically removed tumors to dendritic cells, which are also called antigen-presenting cells because they identify foreign material for destruction by cell-killing T lymphocytes. The tumor cells are cultured with the dendritic cells in the laboratory to enable the immune cells to recognize cancer cells as targets. When the resulting "specialized" dendritic cells are injected back into the patient, they seek out remaining tumor cells and signal for the T lymphocytes to destroy them.

First Study to Prove association of Mobile Phones with Brain Tumours

Wed, 18 May 2005 14:55:00 PST

( from http://www.rxpgnews.com ) The findings are based on a sample of over 1400 adults aged between 20 and 80, living in the centre of Sweden. All of them had been diagnosed with a malignant or benign brain tumour between January 1997 and June 2000.

The group were compared with a similar number of healthy adults, matched for age and sex, and living in the same geographical area.

Daily mobile and cordless phone use was assessed, via questionnaire, which included a complete employment history.

How long users spent on the phone had little impact on the probability of being diagnosed with a brain tumour. But where they lived did make a difference for all phone types, and especially for mobile digital phones.

Residents of rural areas, who had been using a mobile digital phone for more than three years, were over three times as likely to be diagnosed with a brain tumour as those living in urban areas.

And digital mobile phone use for five years or more in a rural area quadrupled the risk compared with residency in urban areas.

For malignant brain tumours, the risk was eight times as high for those living in a rural area, but the numbers were small, caution the authors. No such effect was seen for analogue or cordless phones.

The authors reiterate that there is a difference in power output between mobile phones in urban and rural areas. This is because base stations tend to be much further apart in rural areas, requiring a higher signal intensity to compensate.

The compensatory system, known as the adaptive power control or APC, is used for mobile phone (GSM) networks.

Chromosome Deletion Predicts Outcome in Neuroblastoma Patients

Wed, 18 May 2005 01:45:00 PST

( from http://www.rxpgnews.com ) Researchers from the Children's Hospital of Philadelphia and the Children's Oncology Group found that patients with neuroblastoma who are missing a portion of one of their chromosomes are less likely to survive than those without this genetic aberration, providing potentially important information to guide therapy.

Neuroblastoma is a cancer of the nervous system that mainly affects children and can be very difficult to treat successfully. Although a combination of chemotherapy, radiation therapy, and surgery can help patients with advanced neuroblastoma achieve remission, many patients experience a relapse of their disease.

"Neuroblastoma is easily cured in some children and is very aggressive in others," said Edward F. Attiyeh, MD, a Hematology/Oncology Fellow at Children's Hospital of Philadelphia working in the lab of John M. Maris, MD, and the study's lead author. "However, our tools for determining who is at greatest risk of relapse have been imprecise. This new genetic marker could help identify those patients who could potentially benefit from more intensive therapy."

Investigators analyzed tissue samples from 917 children with neuroblastoma to determine the relationship between disease progression and a deletion in the "q" arm of chromosome 11. Each chromosome has two arms: a long "q" arm and a short "p" arm.

Patients with the 11q deletion were more likely to have their cancer progress or die of the disease. Three years after diagnosis, 50% of those with an 11q deletion experienced progression of their disease or death, compared with 26% of those without this deletion. Fewer patients with chromosome 11q deletion survived three years compared with those without the deletion (65% vs. 83%).

"The identification of this genetic marker can help us better define neuroblastoma, improve our ability to design therapies, and potentially improve patient survival," concluded Dr. Attiyeh. "Our hope is to find one or more genes on chromosome 11q that are involved in the development of aggressive neuroblastoma, and that these specific genes might be useful as therapeutic targets."

Pituitary Gland Tumors Are Often Misdiagnosed

Sun, 01 May 2005 21:04:00 PST

( from http://www.rxpgnews.com ) A recent study found that tumors of the pituitary gland are more common than many health care professionals realize, with national prevalence rates averaging 16.7 percent.

To neurosurgeon Dr. Gail Rosseau, this isn't surprising.

Rosseau, who treats patients with a variety of neurological conditions at Rush University Medical Center and the Chicago Institute of Neurosurgery and Neuroresearch (CINN), says that pituitary tumors are often misdiagnosed because of the confusing array of symptoms they present.

"Conditions such as osteoporosis, sexual dysfunction, depression, infertility, or growth disorders can be the result of abnormalities in the pituitary or "master" gland at the base of the brain. Many times this association is overlooked," Rosseau said.

"These types of tumors are generally not malignant, but they have many different and highly variable ways of making their presence known, "she said. "If misdiagnosed or untreated, they may progress, causing blindness, heart disease or in the worst cases, premature death."

Because the disease is complex, Rosseau saw the need for a patient education association in the Chicagoland area. The Greater Chicago Pituitary Education Association was founded in late 2004 and is underwritten by a grant from The CINN Foundation. Each quarterly meeting of the Association provides an educational presentation from a member of the Chicago medical community involved in the treatment of pituitary disease. The Association aims to include physician speakers ranging from endocrinologists, to neurosurgeons, to ear, nose and throat specialists and bridge institutional alliances.

The next meeting will take place at 6:30 pm on Tuesday, May 3 at The Neurologic & Orthopedic Institute of Chicago, 4501 N. Winchester, ground level.

Many patients are concerned about treatments and surgery because of the location and function of the pituitary. The pituitary is a small, pea-sized gland located at the base of the brain that functions as "The Master Gland." It releases stimulating hormones that signal the thyroid gland, adrenal glands, ovaries and testes, directing them to produce their respective hormones. These hormones have dramatic effects on metabolism, blood pressure, sexuality, reproduction, and other vital body functions. In addition, the pituitary gland produces growth hormone for normal development of height and prolactin for milk production.

CINN psychologist Dino Kostas said pituitary tumor patients have unique concerns, such as loss of vision, that require a different approach. He emphasized that an educational seminar is a great way to allay patient fears while allowing patients to ask questions of anyone on the treatment team.

"Most patients contemplating surgery have fears and concerns about the surgery, but with our patients, we see a heightened level of anxiety about the potential loss of vision because the pituitary gland is so close to the optic nerve," Kostas said. "Frequently, we talk to many patients who are also fearful that they will have decreased libido or become infertile."

Treatment depends on the type of pituitary tumor, the extent to which it has invaded the brain, as well as the patient's age and general health. Treatment is most effective when diagnosis is early, and it typically involves surgery, radiosurgery, and/or drug therapy, Rosseau said.

Ear, nose and throat surgeon Dr. Steven Becker, said that he is able to calm many anxious patients because surgical techniques have vastly improved in the last decade and recovery times are typically one month, down from more than two months previously. Becker has performed approximately 600 of these surgeries.

"As recently as 10 years ago, surgeons would use a craniotomy, which requires an incision under the lip and a full elevation of half the facial tissues to access the nasal interior," he said. "Now, we use an endoscopically assisted approach to access the pituitary gland during the two and half hour surgery. This approach allows surgeons to go up the nasal cavity in a minimally invasive manner," Becker said.

He stressed that surgical candidates are typically those with a past history of sinusitis, or nasal trauma. Becker said that patients who attend the educational forum tend to make for better patients because they ask good questions and the forum helps lessen the anxiety they feel.

CHMP Issues Positive Opinion for First-line Use of Temozolomide in the treatment of Glioblastoma Multiforme

Sun, 24 Apr 2005 08:22:00 PST

( from http://www.rxpgnews.com ) Schering-Plough Corporation (NYSE: SGP - News) today reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has issued a positive opinion recommending approval of TEMODAL® (temozolomide) Capsules for first-line use in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM), the most common form of brain cancer. The CHMP recommendation serves as the basis for a European Commission approval.

TEMODAL is currently approved in the European Union (EU) for the treatment of patients with malignant glioma such as GBM or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

Schering-Plough received full approval of temozolomide (TEMODAR®) from the U.S. Food and Drug Administration (FDA) on March 16, 2005 for the treatment of adult patients with newly diagnosed GBM when administered in combination with radiotherapy and then as maintenance therapy.

A Commission approval would result in centralised Marketing Authorization with unified labeling throughout the EU, covering the use of TEMODAL for the treatment of patients with newly diagnosed GBM concomitantly with radiotherapy followed by up to 6 cycles of temozolomide monotherapy.

The new labeling will be in addition to the currently approved indication, and will be valid in the current 25 EU Member States as well as in Iceland and Norway, once approval is granted by the European Commission.

The positive opinion recommending the labeling expansion for TEMODAL is based largely on efficacy and safety data from a landmark Phase III study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC). These data were published in the March 10, 2005 edition of the New England Journal of Medicine. In this multicenter trial of 573 patients with newly diagnosed GBM, significant improvement in overall survival was observed in patients who were treated with TEMODAL in combination with radiotherapy compared with those treated with radiotherapy alone.

In this study, more than twice as many patients (26 percent) in the TEMODAL group survived two years, compared with 10 percent of those who received radiotherapy alone. Median survival in the TEMODAL group was also significantly better (14.6 vs. 12.1 months) compared to the radiotherapy only group. TEMODAL treatment was generally well tolerated; the most commonly observed adverse events (greater than 10%) in patients receiving TEMODAL in combination with radiotherapy followed by TEMODAL monotherapy included decreased appetite, headache, constipation, nausea, vomiting, hair loss, rash, convulsions and fatigue.

Low white blood cells and low platelets, which are known dose-limiting toxicities for most cytotoxic agents, including TEMODAL, were observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8% of the patients.

Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14% of the patients who received TEMODAL.

Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute, explained that the CHMP approval recommendation reflects the findings of this important, independent study. "This landmark EORTC study clearly demonstrated that TEMODAL offers significant improvement in prognosis for newly diagnosed GBM patients compared with standard treatment, and is safe and well tolerated. This represents an important advance in the treatment of GBM, one of the most serious and aggressive types of malignant brain tumor."

About Temozolomide

Temozolomide is an oral, cytotoxic alkylating agent. Cytotoxic agents are designed to prevent the replication of cells that divide rapidly, including those in tumors. The development of temozolomide for expanded indications is consistent with Schering-Plough's strategy to broaden its oncology portfolio and is in line with its plans to build strength in its global franchises through both internal research and external collaborations and licensing opportunities.

Important Information Regarding U.S. Labeling for TEMODAR with Newly Diagnosed GBM

Patients treated with TEMODAR Capsules may experience myelosuppression.

Grade 3/4 neutropenia occurred in 8% and Grade 3/4 thrombocytopenia in 14% of patients treated with temozolomide.

Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.

TEMODAR Capsules are contraindicated in patients who have a history of hypersensitivity to any of its components, or to DTIC.

Caution should be exercised when administered to those with severe hepatic or renal impairment.

TEMODAR may cause fetal harm when administered to a pregnant woman. Nursing should be discontinued in women receiving TEMODAR.

The effectiveness of TEMODAR in children has not been established.

TEMODAR Capsules should not be opened or chewed. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.

Prophylaxis against Pneumocystis carinii pneumonia (PCP) is required in all patients receiving TEMODAR in combination with radiotherapy for the 42-day regimen. There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. All patients receiving TEMODAR, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

As noted in the U.S. package insert, during the concomitant phase (TEMODAR + radiotherapy), adverse events including thrombocytopenia, nausea, vomiting, loss of appetite and constipation, were more frequent in the TEMODAR + radiotherapy arm versus the radiotherapy arm alone. The incidence of other adverse events were comparable in the two arms.

The most common adverse events across the cumulative TEMODAR experience were hair loss, nausea, vomiting, decrease in appetite, headache and constipation.

No Link Between Cell Phone and Brain Tumors

Tue, 12 Apr 2005 18:02:00 PST

( from http://www.rxpgnews.com ) A new study has found no link between use of cell phones and the risk of developing a brain tumor. The study is published in the April 12 issue of Neurology, the scientific journal of the American Academy of Neurology.

The Danish study questioned 427 people with brain tumors and 822 people without brain tumors about their cell phone use. The study found no increased risk for brain tumors related to cell phone use, frequency of use, or number of years of use.

These results are in line with other large studies on this question, including a recently published large-scale, population-based study by the Swedish Interphone Study Group, said study author Christoffer Johansen, PhD, DMSc, MD, of the Danish Cancer Society in Copenhagen. There have been a few studies that found an increased risk of brain tumors with cell phone use, but those studies have been criticized for problems with the study design.

For 27 people with brain tumors and 47 people without brain tumors, researchers obtained phone records from cell phone companies to document the amount and length of calls and compare the actual calls to what participants reported. Those results found that people accurately remembered the number of calls they made, but did not accurately remember the length of those calls. But there were no differences between the two groups on how well they portrayed their cell phone use. Johansen said that finding minimizes the possibility of what researchers call recall bias, or the chance that people with brain tumor may exaggerate or underestimate their past cell phone use.

Johansen noted that there have been few long-term cell phone users or heavy cell phone users in any of the studies. In our study, few people reported regular cell phone use for 10 years or more, he said. We wont be able to make any firm conclusions until we can confirm these results with studies with more long-term and heavy cell phone users.

The researchers also found that brain tumors did not occur more frequently on the side of the head where the phone was typically used.

Viruses May Treat Brain Tumors

Fri, 08 Apr 2005 01:36:00 PST

( from http://www.rxpgnews.com ) New research shows that a virus designed to kill cancer cells can significantly increase the survival of mice with an incurable human brain tumor, even in some animals with advanced disease.

The study used a genetically altered herpes simplex virus that infects and reproduces only in malignant glioma cells and kills them. The altered virus leaves normal tissues unharmed. Viruses that kill cancer cells are known as oncolytic viruses.

The findings are published in the April 1 issue of the journal Cancer Research.

This is another step toward making oncolytic viruses more effective and safer for use in the treatment of cancer, says E. Antonio Chiocca, professor and chairman of neurological surgery at The Ohio State University Medical Center.

This is a preliminary study, Chiocca emphasized. This virus cannot yet be used in humans. To go from animal studies to human studies is a very long process, especially for a treatment that uses viruses.
The treatment extended the animals lives by several days, Chiocca says. If we could achieve a proportional increase in humans with malignant glioma, that would be a very significant advance.

Malignant gliomas are cancers in the brain that progress quickly after diagnosis. They are nearly always fatal, Chiocca says. The average survival following diagnosis is about a year. They are usually treated using surgery, chemotherapy and radiation.

Unfortunately, the average survival time for these patients has not improved in more than 30 years, says Chiocca, who also directs OSUs Dardinger Center for Neuro-oncology and co-leads the Viral Oncogenesis Program at the OSU Comprehensive Cancer Center. There is a real need for new therapies.

He believes oncolytic viruses offer a promising new strategy.

Chioccas collaborators for the study included Yoshinaga Saeki, associate professor of neurosurgery, who directed the research, and first author Hirokazu Kambara, a post-doctoral fellow.

The study began with a laboratory version of a herpes virus that was missing several genes. The virus could infect only malignant glioma cells, but once inside the cells, it reproduced, or replicated, poorly.

Instead of making 1,000 copies of itself, it might only make 10, Chiocca says. The virus therefore had only a weak ability to kill cancer cells and shrink tumors.

For this study, Saeki, Kambara and Chiocca restored the viruss ability to replicate at high levels by returning one of the genes that had been removed from the virus. First, though, the researchers modified the gene, known as ICP34.5, so that it would be active only in cells that made a protein called nestin.

Why nestin? Usually, cells make nestin only during embryonic development. After that, it is absent from cells. But malignant glioma (and some other cancers) begin producing nestin again. This sets the cancer cells apart from normal cells and gave the researchers the trigger they needed.

The researchers tested the modified virus first in laboratory-grown malignant glioma cells. They found that the ICP34.5 viruses could again replicate at high levels.

Then the researchers tested the virus in mice with implanted human gliomas. In one set of experiments, the researchers gave the virus to the mice early, seven days after implanting the tumors. Untreated mice lived for 21 days after tumor implantation. Eight of 10 mice treated with the ICP34.5 virus survived 90 days after implantation. Two of 10 mice treated with a control virus survived 90 days.

The control virus was very similar to a type used in clinical trials testing viral treatment of malignant glioma. It was similar to the experimental virus, but it lacked the ICP34.5 gene.

But human glioma patients are usually diagnosed and treated later in the disease, after symptoms begin. The researchers therefore conducted an experiment that simulated that condition. They injected the virus into tumors 19 days after implantation and when the mice began showing symptoms, which is similar to the case in human treatment.

In this experiment, two of 10 animals treated with the ICP34.5 virus survived 24 days after implantation. Of mice treated with the control virus, all 10 had died by day 21, a statistically significant difference.

Errant neuro-developmental gene implicated in brain cancer

Thu, 03 Feb 2005 00:49:00 PST

( from http://www.rxpgnews.com ) A gene that's normally silenced after contributing to brain development was found to be expressed in cells from medulloblastoma, the most common form of pediatric brain malignancy in children, scientists report in an article published in the February 1 issue of the journal Cancer Research. In their study, the scientists discovered that multiple extra copies of the gene, called OTX2, had been switched back on among tumor cells removed from patients with medulloblastoma brain tumors. In the United States, medulloblastoma accounts for approximately 30 percent of all pediatric brain tumors.

Further, the scientists discovered that a potent derivative of Vitamin A, known as all trans-retinoic acid or ATRA, suppressed growth and induced cell death among the OTX2-laden tumor cells. More than half of medulloblastomas grown in the laboratory responded to ATRA treatment.

"The response that ATRA imposes upon these medulloblastoma brain tumor cell lines suggests that this type of tumor may respond favorably to ATRA-based therapy," said Hai Yan, M.D., Ph.D., the principle investigator of the study at the Brain Tumor Center at the Duke University Medical Center.

"ATRA is already clinically approved for the treatment of acute promyelocytic leukemia. These studies lay the conceptual and practical framework for clinical trials using ATRA in the treatment of a commonly lethal pediatric disease."

Yan said that the OTX2 gene normally contributes to development and growth of certain areas of the brain, such as the cerebellum, but the gene is generally turned off and no longer used after birth.

Using a novel technique that involves snipping apart the entire DNA content in the chromosomes of medulloblastoma cells and then analyzing the quantity of each, Yan and his colleagues detected an abnormally amplified segment among the tumor cells on chromosome 14.

"There was a striking amplification of genetic coding representing a 28-fold increase in base pairs of DNA in that specific region of chromosome 14," Yan said. The researchers identified OTX2 as the only gene contained within the amplified region of the chromosome.

The scientists also determined that 60-70 percent of the medulloblastoma cells were churning out large numbers of messenger RNA specific for OTX2, compared to normal cells which generally show no activity for this gene.

This latter finding suggested another approach, RNA interference, to blocking OTX2 activity. Discovered in the late 90's, RNA interference or RNAi refers to the introduction of double-stranded RNA (dsRNA) into a cell, where it induces the degradation of complementary messenger RNA, thereby suppressing the gene expression.

"In our studies, we applied several specifically designed RNAi to the tumor cells that expressed OTX2," Yan said. "We then observed that the RNAi knocked down OTX2 expression and killed the tumors cells which expressed OTX2. In contrast, the RNAi did not do any damage to the cells which did not express OTX2."