RxPG News : Lung

Genetic variation-Lung cancer drugs work better in the Japanese than in the Americans

Sun, 03 Jun 2007 03:30:05 PST

( from http://www.rxpgnews.com ) Last year, a groundbreaking international project found that a group of Japanese patients with advanced non-small cell lung cancer survived longer âand had a higher rate of side effects â than U.S. patients with the same diagnosis,.when both groups were given two well-known drugs for the disease.

Now, a follow-up study suggests the reasons appear to lie in subtle variations in certain genes that govern how the body metabolizes chemotherapy drugs. David Gandara, M.D., a University of California, Davis researcher who led the recent Southwest Oncology Group study, presented the results Saturday, June 2, at the American Society of Clinical Oncology annual meeting.

The discovery that Japanese and U.S. patients, matched in age, gender and other respects, had differences in key metabolism-related genes is the latest result from a seven-year collaboration between the Southwest Oncology Group and two clinical trials groups in Japan. Gandara, who leads lung cancer trial efforts for the Southwest Oncology Group, is director of clinical research at the University of California, Davis, Cancer Center. The Southwest Oncology Group (SWOG) is the largest federally funded U.S. cancer trials network.

The recent SWOG study breaks new ground by exploring the possible role of ethnic patterns in the emerging science of pharmacogenomics, which promises to tailor drug regimens to a patientâs genetic profile. âNobody else in the world has ever done this, with a common arm looking at genetic differences among ethnic groups,â Gandara says.

Researchers looked at DNA from 156 patients who received the chemotherapy drugs paclitaxel and carboplatin in a SWOG clinical trial and one conducted by the Japan Multicenter Trial Organization. In the trials, half the Japanese patients survived one year, while slightly more than one-third of U.S. patients did. The Japanese patients as a group survived longer despite the fact that a significant number of them had to be given a lower dose of paclitaxel and for a shorter time than the U.S. patients because of toxicity. The U.S. group was predominantly Caucasian; 2 percent were Asian-Americans.

To find clues to the differences, the scientists examined six genes in DNA samples from the patients. They found differences in four. In patients with certain variations in the CYP3A4 gene, it took 2.75 times longer for their lung cancer to progress than in patients without the variations. A variation in another gene, ERCC2, appeared to interfere with how well patients responded to treatment.

The differences in outcomes corresponded with the patientsâ genetic makeup, rather than their ethnicity per se, since. some individuals in each group possessed genetic variations not typical of their group. Thus, the study suggests therapies in the future need to be tailored to each individual based on analysis of his or her genetic makeup, not simply ethnicity.

The relatively small number of patients makes the results of the study far from conclusive: Gandara calls the study âhypothesis-generating.â Next, he and other SWOG scientists are seeking funding to learn what genes may explain why Japanese and U.S. patients respond differently to EGFR inhibitors such as erlotinib, a relatively new targeted therapy that is another important class of drugs for lung cancer.

Ireland Cancer Center researchers advance lung cancer treatment

Mon, 23 Apr 2007 12:38:55 PST

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

Tarceva is among a new generation of cancer therapies that disrupt the molecular target responsible for stimulating tumor growth. The drug targets the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells.

Researchers at the Ireland Cancer Center of University Hospitals Case Medical Center have developed methods for treating lung cancer cells that have become resistant to new anti-cancer agents.

Led by Balazs Halmos, MD, hematologist/oncologist with the Ireland Cancer Center, the research team followed up on their previous study, published in the New England Journal of Medicine, which found that lung cancer cells can become resistant to novel targeted agents, such as Tarceva (erlotinib), a medication in widespread use for non-small-cell lung cancer (NSCLC). Tarceva is among a new generation of cancer therapies that disrupt the molecular target responsible for stimulating tumor growth. The drug targets the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells. Clinical applications of the new drug initially yielded good results with approximately 10 percent of patients experiencing complete remission of their disease.

However, in spite of the therapy's initial success, patients inevitably suffered a relapse of their disease. Dr. Halmos' studies confirmed the existence of a mutation, and insertion of this mutation into test cells rendered them resistant to Tarceva. These cells became resistant by undergoing a miniscule molecular change in the EGFR protein that the medication targets. Further analysis revealed that the newly identified mutation was altering the protein's drug-binding pocket and thereby changing the "keyhole" so that the "key" â Tarceva â no longer fit. The researchers found that new second-generation Tarceva-like medications can overcome this change and such drugs are now in development, including in clinical trials at the Ireland Cancer Center.

In this latest study, that received an award at the annual American Association for Cancer Research (AACR) meeting where it was presented earlier this month, Dr. Halmos and his team were able to predict molecular changes the tumors might take next to become resistant to this new class of agents. "We tried to outsmart tumors by anticipating their next moves," says Dr. Halmos, a lung cancer specialist and Assistant Professor of Medicine at Case Western Reserve University School of Medicine. "This research revealed a number of new changes that EGFR can undergo that leads to resistance and also found ways to conquer this next generation of mutants."

The research team developed compounds to overcome the resistance with innovative combinations of medications. "Using these combinations early on can prevent resistance," explains Dr. Halmos. "Through this research, we are redefining our tools and anticipating ways to fight lung cancer."

Other significant presentations at AACR by Ireland Cancer Center physicians include:

Dr. Sanford Markowitz and Dr. Halmos identified a gene, PGDH, known to be important in controlling colon cancer cell growth as a protein that participates in the growth pathways regulated by an important lung cancer "brake" gene, HNF3beta. PGDH is an enzyme that regulates the amount of certain hormone-like substances called prostaglandins in the tissues and bloodstream. This activity can be modified by medications that may prove effective in cancer treatment.

Dr. Patrick Ma and his research team have identified a unique genetic mutation in the receptor protein EGFR that desensitizes the response to Tarceva (erlotinib) but yet differentially sensitized the response to another medication, Iressa (gefitinib), further. The mutation was initially identified in one of Dr. Ma's patients who responded dramatically to Iressa prescribed for her terminal complication from her lung cancer metastatic to the spinal cord (leptomeningeal metastasis), a case that was recently published in the Nature Clinical Practice Oncology. Dr. Ma's team conducted further study on the mutation and identified the mutation to occupy a location that constitutes a highly conserved salt bridge structure across the whole human kinome (more than 300 protein kinases with many of which as "druggable" therapeutic targets). His findings suggest that genetic mutations altering the salt bridge structure in the kinome proteins may affect cancer cell signaling, drug inhibitor binding and drug sensitivity. Theses insights would have wide implications in the principle of novel targeted cancer therapeutics. Dr. Ma's team also continues to make promising progress in their work on the development of alternative targeted therapeutics against a novel receptor target c-MET with the goal of optimizing lung cancer treatment, especially in those with resistance to EGFR inhibitors.

Lung cancer screening regimen provides opportunity for cure

Tue, 27 Mar 2007 01:09:42 PST

( from http://www.rxpgnews.com ) Annual computed tomography (CT) screening identifies a high proportion of patients with early-stage lung cancer, according to the latest findings of the New York Early Lung Cancer Action Project (NY-ELCAP) published in the April issue of the journal Radiology.

âThe regimen of screening determines how early the cancer is diagnosed. This is critical, as it provides the opportunity for earlier treatment which can be curative,â said NY-ELCAP principal investigator Claudia I. Henschke, Ph.D., M.D., professor of radiology at Weill Cornell Medical College and chief of the divisions of chest imaging and health care policy and technology assessment at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York City. âFollowing the appropriate regimen also markedly decreases unnecessary work-up and biopsies,â she added.

Lung cancer remains the leading cause of cancer death in both men and women, killing more people than breast, prostate and colon cancers combined, according to the American Cancer Society (ACS). According to the study, the estimated cure rate for lung cancer in the absence of screening is approximately 5 percent, but increases significantly when the cancer is diagnosed and treated at its earliest stage.

NY-ELCAP investigators at 12 medical institutions in New York State provided baseline (first-time) CT screenings to 6,295 people with no symptoms of cancer. The participants were age 60 or older with a history of smoking but no prior cancer and no chest CT in the past three years. A total of 6,014 annual repeat screenings were provided.

CT results prompted recommendations for further work-up on 14 percent of the 6,295 baseline screening participants and 6 percent of the 6,014 repeat screening participants.

A total of 124 people were diagnosed with lung cancer, all but three directly based on screening results, rather than interim symptom-prompted diagnoses. A high proportion of the 124 patients (89 percent in the baseline and 85 percent in the repeat rounds of screening) had no evidence of metastases when recommended for biopsy, indicating that a regimen of annual repeat screenings allows for detection of lung cancer at its earliest, most treatable, stage. Long-term follow-up, as shown in an International ELCAP study recently published in the New England Journal of Medicine, demonstrated a 10-year survival rate of 92 percent among patients with Stage 1 lung cancer when diagnosed early and promptly treated.

âIt is critical that physicians and the people being screened understand the importance of following an optimal screening regimen,â Dr. Henschke said. âDelay in the recommended diagnostic work-up detracted from the full benefit of CT screening, as it resulted in progression of the cancer in size, and sometimes resulted in a higher stage of the disease.â

While a recent JAMA study has suggested that screening CT does not reduce mortality rates for lung cancer, Dr. Henschke disagrees. âThe JAMA article was the first application of a newly developed computer model which predicted expected deaths from lung cancer, and there are numerous concerns about its validity,â she said. âThe main problem with that study is that it focused on too short a time period to assess the decrease in lung cancer deaths, which starts to be evident after the first five years of screening.â

Dr. Henschke recommends that smokers and former smokers considering CT screening should talk to their physicians and, if they decide to be screened, go to an imaging facility with a multidisciplinary team of physicians knowledgeable and experienced in CT lung screening.

MEK inhibitors may be beneficial for lung cancer containing mutations in the BRaf gene

Tue, 13 Feb 2007 03:38:12 PST

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

The use of a relatively new class of drugs, called MEK inhibitors, for lung cancer patients whose tumors contain mutations in the BRaf gene.

In a new report in the February 15th issue of G&D, Dr. Martin McMahon (UCSF) and colleagues present a novel mouse model of non-small cell lung cancer, which will serve as a useful tool to test the efficacy of novel chemotherapeutic drug therapies in the early stages of lung tumorigenesis. Their paper provides evidence to support the use of a relatively new class of drugs, called MEK inhibitors, for lung cancer patients whose tumors contain mutations in the BRaf gene.

BRaf is one of three members of the RAF kinase family, which, upon activation, induces the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) cell signaling pathway and promotes cell proliferation. Activating mutations in BRaf (ie., a mutation that causes the activation of the catalytic activity of the BRaf protein) are implicated in a number of different human cancers, including the majority of melanoma cancers, as well as in colorectal, thyroid, ovarian and non-small cell lung cancers.

Dr. McMahon and colleagues engineered a strain of mice to carry a version of the BRaf gene that the researchers could activate at will both temporally and spatially. After activating BRaf specifically in the lungs of mice at 6-8 weeks of age, the researchers observed that the BRaf-mutant mice (or BRaf(VE), as they are known) developed multiple lung tumors that were pathologically similar to human lung tumors thereby establishing BRaf as a bona fide oncoprotein.

Administration of the MEK-inhibitor, PD0325901 (developed by Pfizer, and now in clinical trials) effectively halted tumor progression in BRaf(VE) mice. Interestingly, however, without pharmacological intervention, the BRaf-mutant tumors eventually stopped proliferating, and entered into a senescent state. This senescent state could be overcome by concomitant mutation of either p53 or p16(Ink4a)/p19(Arf), enabling tumors to become adenocarcinomas.

Dr. McMahon said that the striking response of BRaf(VE)-induced lung tumors to MEK inhibition is most likely because the tumors are at such an early stage of their development. Such observations further emphasize the need for early detection in human lung cancer, since the earlier a tumor is detected the more likely it is to be curable. However, MEK inhibitors may still be useful for late stage cancers, especially if used in conjunction with conventional chemotherapy, a question that McMahon and colleagues are planning to address in their next round of experiments.

Potential solution to cetuximab-resistance in lung cancers

Sun, 28 Jan 2007 04:06:22 PST

( from http://www.rxpgnews.com ) Antibodies that selectively bind and destroy cancer cells represent some of the most promising cancer therapy approaches being developed today. Several of these antibodies have reached the market, including cetuximab (Erbitux®, ImClone Systems), which targets the epidermal growth factor receptor (EGFR) protein. However, a study conducted at the Dana-Farber Cancer Institute and the Ludwig Center at Dana-Farber/Harvard Medical School now suggests that antibodies binding a particular protein conformation, caused by hyperactivation, might have distinct therapeutic advantages over antibodies, like cetuximab, that bind to wild-type (normal) target proteins.

The study, led by Dana-Farber Cancer Institute's Dr. Kwok-Kin Wong, and published today in the Journal of Clinical Investigation, is part of a multi-center, international effort to assess the clinical potential of the 806 antibody. The 806 antibody was discovered by scientists at the Ludwig Institute for Cancer Research. The antibody targets EGFR only when the receptor has been activated by mutations, by the protein's over-expression or by amplification of the EGFR gene. In the present study, Dr. Wong compared the action of cetuximab and 806 in a mouse model of non-small cell lung cancer (NSCLC) caused by different activating mutations in EGFR.. The 806 antibody caused a dramatic tumor regression in the mice, while cetuximab did not.

"Cetuximab only works on a subset of patients with lung cancers," says Wong. "We think the 806 antibody might benefit those patients who respond to cetuximab but, more importantly, might also be effective for those patients who don't." According to Dr. Wong, approximately 10-30 percent of patients with NSCLC and 5 percent of patients with squamous cell lung cancers have EGFR activating mutations. Some brain tumors also have EGFR activating mutations that are – in animal studies – responsive to the 806 antibody. A phase I clinical trial of the 806 antibody has been completed in Melbourne, Australia by the Ludwig Institute for Cancer Research co-authors. The antibody was shown to target a variety of cancers, including squamous cell lung cancer, with no targeting of normal tissues and no toxicity.

Gene Expression Profiling Not Quite Perfected in Predicting Lung Cancer Prognosis

Fri, 17 Nov 2006 13:30:37 PST

( from http://www.rxpgnews.com ) While there have been significant advances in the use of gene expression profiling to assess a cancer prognosis, a Mayo Clinic review and analysis of existing lung cancer studies shows that this technology has not yet surpassed the accuracy of conventional methods used to assess survival in lung cancer patients.

The interest in and the knowledge of gene expression profiling in medical science has exploded since the completion of the human genome project in 2003. Researchers caution that the science of gene expression profiling, in which scientists examine the genetic signature of a cell, is in its infancy, particularly in lung cancer.

"Growing evidence suggests that gene-based prediction is not stable and little is known about the prediction power of a gene expression profile as compared to well-known clinical and pathologic predictors," according to Ping Yang, M.D., Ph.D., the corresponding author of the study that appears in the November issue of Cancer Epidemiology, Biomarkers and Prevention (CEBP). The study's first author is Zhifu Sun, M.D., a research associate with the Department of Health Sciences Research at Mayo Clinic.

Dr. Yang, a researcher with Mayo Clinic's Department of Health Sciences, said that while gene expression profiling has been successfully used to classify various tumors and assess tumor stage, metastasis and patient survival rates, the evidence suggests that gene-based prediction for lung cancer is not yet entirely dependable. However, some results have been promising: gene profiling has reliably predicted patient survival for lung adenocarcinoma almost as well as established predictors.

The results of conventional methods that factor in age, gender, stage, cell type and tumor grade outweigh the predictive advantage of a gene expression profile. "Any new technique that does not significantly outperform less expensive and easily conducted approaches is less likely to be useful in clinical practice," the authors wrote.

Few studies have compared conventional methods of lung cancer prediction with gene profiling. It remains to be seen whether gene expression profiling of lung cancer cases can replace or augment the existing assessment tools and, furthermore, whether it can lead to improved patient care.

In terms of problems associated with gene expression profiling in lung cancer research, the authors found:

* The accuracy of gene expression-based outcome prediction varies greatly among studies.
* Most studies lacked independent validation.
* Clinical outcome prediction between gene expression profiles and pathological features overlap significantly.
* Current analytical algorithms favor genes at high expression or genes highly differentially expressed, most of which are related to tumor differentiation and may not correlate with clinical outcomes; conversely, genes expressed at low levels or in a subtle difference are often overlooked, which may be quite relevant biologically to clinical questions.

The authors of the study recommend that medical scientists engaged in gene expression profiling should:

* Clearly define a study aim. The main focus in microarray studies should explore the molecular explanations for varied clinical outcomes given a group of patients with similar clinical and pathological characteristics.
* Lay out and compare alternative study designs
* Carefully select samples in terms of size, quality and unambiguous clinical outcomes
* Understand the limitations of DNA microarray
* Provide clinically relevant interpretation from the study results and address the value added in practice

I-ELCAP study: Lung cancer can be detected early with annual low-dose CT screening

Thu, 26 Oct 2006 19:23:37 PST

( from http://www.rxpgnews.com ) Lung cancer can be detected at its very earliest stage in 85 percent of patients using annual low-dose CT screening, and when followed by prompt surgical removal, the 10-year survival rate is 92 percent. These results, to be reported in the October 26 New England Journal of Medicine, would dramatically decrease the number of deaths from lung cancer the number one cause of cancer deaths among both men and women in the U.S.

The study was launched by a team of researchers at New York-Presbyterian Hospital/Weill Cornell Medical Center in 1993 and has expanded into an international collaboration of 38 institutions in 7 countries, the International Early Lung Cancer Action Project (I-ELCAP). The I-ELCAP study is the largest, long-term study to determine the usefulness of annual screening by CT.

Stage I lung cancer is the only stage at which cure by surgery is highly likely. While survival rates have been climbing for other forms of cancer, the survival rates for lung cancer have remained dismal. Approximately 95 percent of the 173,000 people diagnosed each year die from the disease more than breast, prostate and colon cancer combined. The high death rates are a consequence of lung cancer not being detected early enough for treatment to be curative.

Among the 31,567 people in the study, CT screening detected 484 people who were diagnosed with lung cancer, 412 of whom were Stage I. Of the Stage I patients who chose not to be treated, all died within five years. Overall, the estimated 10-year survival rate for the 484 participants with lung cancer was 80 percent. The participants were 40 years of age and older and at risk for lung cancer because of a history of cigarette smoking, occupational exposure (to asbestos, beryllium, uranium or radon), or exposure to secondhand smoke.

"We believe this study provides compelling evidence that CT screening for lung cancer offers new hope for millions of people at risk for this disease and could dramatically reverse lung cancer death rates," said Dr. Claudia Henschke, the study's lead author and principal investigator who is chief of the chest imaging division at NewYork-Presbyterian/Weill Cornell and professor of radiology and cardiothoracic surgery at Weill Cornell Medical College.

Since the early 1990s, there have been remarkable advances in CT scanners. Sub-millimeter "slicing" can now be applied to the entire chest in a single breath-hold. As a result, lung cancer may be detected when it is smaller than it was possible to diagnose previously. Although CT scans once yielded only 30 images, current technology yields over 600 images. As the technology advanced, the approaches for studying the usefulness of this technology have also advanced.

The charge for a low-dose CT screening varies, but ranges from $200 to $300. Treatment for Stage I lung cancer is less than half the cost of late-stage treatment. Estimates of the cost-effectiveness of CT screening for lung cancer are similar or better than those for mammography screening for breast cancer.

Key to lung cancer chemotherapy resistance revealed

Wed, 11 Oct 2006 05:35:37 PST

( from http://www.rxpgnews.com ) Scientists at Johns Hopkins have discovered how taking the brakes off a "detox" gene causes chemotherapy resistance in a common form of lung cancer.

Products made by a gene called NRF2 normally protect cells from environmental pollutants like cigarette smoke and diesel exhaust by absorbing the materials and pumping them out of the cell. Another gene called KEAP1 encodes products that stop this cleansing process. But lung cancer cells sabotage the expression of these same genes to block assault from chemotherapy drugs.

"What we're seeing is that lung cancer cells recruit and distort NRF2 and KEAP1 expression to help tumor cells evade the toxic effects of chemotherapy," says Shyam Biswal, Ph.D., associate professor at the Johns Hopkins Bloomberg School of Public Health and Kimmel Cancer Center, who published results of cell culture studies in the October 3, 2006 issue of PLoS Medicine.

Past studies have shown that NRF2 detoxifies cells by directing proteins to absorb and pump out pollutants and chemicals. The NRF2 gene makes a "trigger" protein which starts the production of other proteins and enzymes that sweep the cell clear of toxins. To halt the detox process, proteins manufactured by KEAP1 bind to the NRF2 triggers tagging them for destruction. In cancer cells, NRF2 activity runs amok, sweeping away all cellular toxins, including chemotherapy agents.

Biswal says that blocking NRF2 activity could improve the effectiveness of standard chemotherapy drugs, particularly platinum-based compounds widely used for lung cancer.

In Biswal's study, half of 12 lung cancer cell lines and 10 of 54 tissue samples from non-small cell lung cancer patients had mutations in the KEAP1 gene rendering it inactive and unable to keep NRF2 activity in check. In addition, half of the tissue samples were missing one copy of the KEAP1 gene - cells usually have two copies of each gene. No missing genes or mutations were observed in normal lung tissues from the same patients.

NRF2 activity along with its cleansing proteins and enzymes were higher in tumor samples than normal cells, according to the researchers. Their cell culture tests also show that cancer cells with KEAP1 mutations are more resistant to chemotherapy drugs than normal lung cells.

Tumor samples with normal KEAP1 genes also show increased levels of NRF2 and its enzymes, suggesting other ways of dismantling KEAP1, such as splicing the gene to make a shortened, ineffective protein, he said.

3D-CRT brings hope for inoperable lung cancers

Fri, 01 Sep 2006 17:33:37 PST

( from http://www.rxpgnews.com ) Modern three-dimensional radiation therapy has been proven to be more successful at curing lung cancer than older two-dimensional radiation therapy for some patients with early stage lung cancer, according to a new study in the September 1, 2006 edition of the International Journal of Radiation Oncology * Biology * Physics, the official journal of the American Society for Therapeutic Radiology and Oncology (ASTRO).

Non-small cell lung cancer (NSCLC) accounts for 87 percent of all lung cancers diagnosed. Currently, the best treatment for stage I NSCLC is surgery or stereotactic radiation therapy (SRT), often followed by chemotherapy if the lesion was larger than 3 cm or radiotherapy and chemotherapy if the surgical margin or hilar or mediastinal nodes were positive at the time of operation. The five-year survival outcomes are very high, with 50 to 67 percent of these patients living at least five years after diagnosis if patients had a well staged stage I NSCLC. When surgery is not an option because the patient has heart problems or other complications, treatment options include varying types of radiation therapy and chemotherapy, alone or in combination.

In this study, doctors at M.D. Anderson Cancer Center in Houston wanted to see if conventional radiation therapy worked as well as the newer three-dimensional conformal radiation therapy (also called 3D-CRT) at curing patients with early stage non-small cell lung cancer. 3D-CRT was created to improve upon older types of radiation therapy by allowing doctors to aim several radiation beams at the tumor to shape or "conform" the radiation to the lung. The idea is that tailoring each beam allows doctors to give more radiation to the tumor while keeping it away from nearby healthy tissues.

Between 1978 and 2003, 200 patients with medically inoperable stage I NSCLC were treated with radiation therapy alone. Eighty-five received 3D-CRT while 115 received conventional therapy. Thirty-six percent of patients who received 3D-CRT lived five years after diagnosis compared to 10 percent who received the conventional therapy. Their causes of deaths were more related to intercurrent disease rather than cancer. Local failure was significantly reduced by 3D-CRT compared to conventional RT.

"This study proves that three-dimensional conformal radiation therapy improves outcomes for patients with medically inoperable stage I non-small cell lung cancer," said Ritsuko Komaki, M.D. "Patients with this type of lung cancer should ask their radiation oncologist about 3D-CRT." Dr. Komaki is a radiation oncologist and professor at M.D. Anderson Cancer Center in Houston.

Sunitinib Malate shows promise against advanced form of lung cancer

Mon, 05 Jun 2006 16:30:37 PST

( from http://www.rxpgnews.com ) Results of a multi-center clinical study of a drug currently approved for treatment of kidney cancer indicate that it may also be effective for people with recurrent and advanced lung cancer.

The findings of this phase-2 clinical trial will be presented at the American Society of Clinical Oncology (ASCO) meetings in Atlanta on Sunday (June 4).

Dr. Mark A. Socinski, associate professor of medicine at the University of North Carolina at Chapel Hill and a clinical faculty member of the UNC Lineberger Comprehensive Cancer Center, is the study's principal investigator. Socinski said the activity data on Pfizer's oral drug, sunitinib malate, appears "very similar" to that of other currently approved agents for non-small cell lung cancer.

Another drug, Avastin, keeps new blood vessels from forming and has been shown to help people with advanced lung cancer live longer when it was given along with chemotherapy.

Sunitinib, which is also an anti-angiogenic agent, interferes with a tumor cell's ability to develop new blood vessels. It acts on a molecular level by inhibiting an enzyme tyrosine kinase that activates cellular growth factor receptors, thus preventing further blood vessel growth.

"As a single agent, this drug worked in a difficult group of patients whose advanced disease had been previously treated with other chemotherapies and whose options were limited," Socinski said.

According to the UNC thoracic oncologist, among 63 patients treated, there were six confirmed partial responses, with disease stabilized in an additional 27. He said data as to length of survival "are still pending."

The patients were enrolled in the trial from January to October 2005. Treatment involved one 50-milligram oral dose (pill) per day for four weeks followed by two weeks off treatment, thus a six-week treatment cycle.

Adverse affects (toxicities) of the drug include fatigue, nausea, vomiting, abdominal pain and high blood pressure. Two patients developed a pulmonary hemorrhage and one a cerebral hemorrhage.

After the initial 63 patients, 47 more have been treated on a continuous dose of the drug, at 37.5 milligrams per day. This extension of the clinical trial will explore the effectiveness and safety of a continuous dosing strategy, Socinski said.

Tarceva-Celebrex Combination therapy shows promising results in advanced lung cancer

Thu, 01 Jun 2006 13:40:37 PST

( from http://www.rxpgnews.com ) An early phase study pairing an experimental targeted therapy with a common anti-inflammatory produced promising results in patients with advanced lung cancer, researchers at UCLA's Jonsson Cancer Center reported.

Pairing the targeted therapy Tarceva with the anti-inflammatory drug Celebrex increased response rates in lung cancer patients by about three-fold, said Dr. Karen Reckamp, an assistant professor of hematology/oncology and lead author of the study. The research appears in the June 1 issue of Clinical Cancer Research, the peer-reviewed journal of the American Association of Cancer Research.

Previous laboratory studies at UCLA showed that a cell signaling pathway known as COX-2 may be linked to resistance to drugs like Tarceva, which block tumor cell growth by targeting the protein EGFR, or epidermal growth factor receptor. Researchers theorized that giving Tarceva with Celebrex, a COX-2 inhibitor, would help battle resistance and prove to be an affective combination against lung cancer.

Typically, about 10 percent of lung cancer patients respond to Tarceva. In Reckamp's study of the combination therapy, about 33 percent of patients responded.

"Tarceva alone is a great drug and has a lot of clinical benefits, but for a small proportion of patients," Reckamp said. "With this drug combination, we saw an increase in response rates, indicating we are overcoming some resistance. We also may be beginning to understand the mechanisms of that resistance."

Volunteers in the Phase I study, patients with advanced lung cancer that had failed to respond to all conventional therapies, took several Celebrex pills and one Tarceva pill each day. After eight weeks, researchers looked at response rates. Patients were able to stay on the study as long as they didn't experience tumor growth. The longest duration of response was 93 weeks, Reckamp said, about three to four times longer than the average duration of response for a patient with advanced lung cancer.

The study was part of the Specialized Program of Research Excellence (SPORE) in lung cancer at UCLA's Jonsson Cancer, a program funded by the National Cancer Institute at top research institutions nationwide to find better and more effective ways to prevent, detect and treat lung cancer.

"This trial is an important early step in utilizing combination targeted therapies in lung cancer," said Dr. Steven Dubinett, director of UCLA's lung cancer SPORE and a professor of pulmonary and critical care medicine. "Dr. Reckamp's trial is the first to study increasing doses of a COX-2 inhibitor in lung cancer in an attempt to define an optimal biological dose. Larger trials of combination therapies utilizing this dose will now be required."

The biology of an individual's tumor determines whether they will respond to Tarceva. Because researchers don't yet fully understand what biologic characteristics determine response, they can't test patients first to determine who should be given the drug. Since 90 percent of patients don't respond to Tarceva, the drug was not an option for them. Reckamp said a portion of those may now be able to take Tarceva combined with Celebrex.

Because they target what is broken in a cancer cell and leave the healthy cells alone, therapies like Tarceva cause fewer side effects than conventional therapies such as chemotherapy, which targets all fast growing cells and often results in debilitating side effects. Reckamp characterized the side effects seen with the combination therapy as minor.

The next step is a larger Phase II study to confirm the efficacy of the combination therapy and further probe the mechanisms of Tarceva resistance, Reckamp said. That study is expected to begin at UCLA in the fall.

Reckamp's study was the first to determine the safest and most effective dose of Celebrex to use in lung cancer. Previously, doses were based on studies done in colon cancer patients.

"I think the results of this early phase study are promising and I anticipate we'll have a better understanding of Tarceva resistance in the near future," she said.

Lung cancer is the most common cause of cancer-related death in both men and women and accounts for about 29 percent of all cancer deaths. This year alone, 174,470 people will be diagnosed with lung cancer in the United States. Of those, 162,460 will die, according to the American Cancer Society.

Only about 15 percent of people who get lung cancer reach five-year survival. Those with advanced disease usually survive less than a year.

"It's crucial that we develop better treatments for this disease," Reckamp said.

Lung cancer susceptibility runs in families - Study

Mon, 03 Apr 2006 06:58:37 PST

( from http://www.rxpgnews.com ) Studying thousands of people, researchers at The University of Texas M. D. Anderson Cancer Center have documented a 25 percent increased risk of developing one of a number of cancers in first-degree relatives of lung cancer patients who have never smoked compared to families of people who neither smoke nor have lung cancer.

Researchers say their study, one of the largest ever done and the only one to include both men and women, strongly suggests that these lung cancer patients and their affected relatives share an inherited genetic susceptibility to cancer development.

"This study demonstrates the importance of familial factors in the general development of cancer," says the study's first author, Olga Gorlova, Ph.D., assistant professor in the Department of Epidemiology. "These susceptibility factors can be environmental, but are more likely to be influenced by genetic factors, because genes control pathways common to a number of cancers."

Such marked cancer susceptibility also likely explains why patients in this study, who never smoked but might have been exposed to secondhand smoke, developed lung cancer in the first place, she says. Gorlova will present the study at the annual meeting of the American Association for Cancer Research (AACR). She will discuss the findings in a press briefing on Tuesday, April 4, 2006 at 11 a.m.

The research team, headed by Margaret Spitz, M.D., professor and chair of the Department of Epidemiology, looked at whether 2,465 first-degree relatives of 316 lung cancer patients who never smoked developed cancer. They also established a matched comparison group of 2,442 first-degree relatives of 318 "controls" - individuals who also never smoked but did not have lung cancer. (An individual's first-degree relatives include his/her parents, children and siblings - people who share one-half of that individual's genes.)

The median age of both cases (patients) and controls was about 61 years, and the median number of first-degree relatives was eight for both groups.

The researchers compared cancer incidence between the two groups adjusting their findings to eliminate the influence of age, gender, ethnicity and smoking status.

They discovered:

* First-degree relatives of cases had a 25 percent increased risk of developing any type of cancer, compared to controls. Cancers diagnosed in the relatives include melanoma, colorectal, head and neck cancer, lung, prostate and breast cancers.
* Case relatives were about 10 years younger when they were diagnosed with cancer, compared to control relatives.
* A 44 percent excess risk of young onset cancers - those diagnosed before age 50 - among case relatives.
* More than a six-fold risk of developing young onset lung cancer in the case families compared to control families.
* Relatives of case patients had a 68 percent increased risk of developing lung cancer.
* Mothers of case patients had more than a two-fold risk of developing breast cancer.

"It has long been observed that cancer seems to occur in some families more than in others, and with the help of this unique group of lung cancer patients and their relatives, we can begin to understand why that might be the case," says Spitz.

The research team plans next to compare specific genes, such as those that help repair DNA damage, between the groups.

Do Variants in the GST Detoxification Genes Affect the Risk of Lung Cancer?

Wed, 08 Mar 2006 05:10:37 PST

( from http://www.rxpgnews.com ) By the year 2020, global deaths from noncommunicable diseases are expected to increase by 77%. The projected rise is mainly due to the aging of the population and to an increase in the numbers of people exposed to tobacco. While antismoking campaigns have met with some success in developed countries, the tobacco epidemic is growing in many of the world's developing and most populous countries. Tobacco (a major risk factor not only for lung cancer but also for chronic obstructive pulmonary diseases such as emphysema) is expected to kill more people than any single disease, surpassing even the HIV epidemic.

The link between tobacco smoke and lung cancer is striking, but not all smokers get lung cancer, and not all lung cancer patients have a history of first- or second-hand exposure to tobacco smoke. Tobacco smoke contains carcinogens such as benzopyrene, which can cause mutations in the DNA of cells it comes in contact with, such as lung epithelial cells. Cytosolic enzymes such as those of the glutathione S-transferase (GST) family are part of the human body's armor against environmental carcinogens; they catalyze the detoxification of reactive electrophilic compounds like benzopyrene. Like all human genes, those encoding members of the GST family exist in multiple variant forms or alleles. Some of these alleles encode less-active or completely inactive versions of the detoxifying enzymes, and, therefore, might convey increased risk for the development of cancers with strong environmental determinants, and lung cancer in particular.

Although more than 100 studies have tested the hypotheses that particular GST alleles either predispose to or protect against lung cancer, the results have been inconsistent, with some studies reporting strong associations and others failing to replicate these findings. Individual association studies are notoriously prone to error, and attempts to combine results from several studies have been complicated by the fact that allele frequencies for many of the alleles differ between populations, by differences in smoking habits, and by differences in criteria for the selection of suitable control groups.

To summarize the current evidence comprehensively and attempt to resolve the controversy, Zheng Ye and colleagues undertook a large meta-analysis of 130 published studies that had examined associations between one or several of five GST alleles and lung cancer. The five alleles included the GSTM1 and GSTT1 null alleles, two missense alleles in GSTP1, and one intron polymorphism in GSTM3. (The null alleles abolish enzyme activity; the three other alleles encode enzymes with reduced activity.) A total number of 23,452 lung cancer cases and 30,397 controls were included in the meta-analysis. Ye and colleagues corresponded with the individual research groups to obtain the data in tabular form andfor a few of the studiesadditional data that were not included in the original publications.

When taking all the existing evidence together, neither the I105V or A114V polymorphisms in GSTP1 nor the GSTM3 intron 6 polymorphism were found to be associated with increased risk of lung cancer. The two null polymorphisms in GSTM1 and GSTT1 showed a weak association. However, as Ye and colleagues discuss, it is possible that the weak overall link results from bias toward publication of positive results, especially for smaller studies. This is consistent with the result that the researchers obtained when they restricted their analysis to larger studies: comparing only cases and controls from studies that had at least 500 participants resulted in no significant associations between any of the alleles and lung cancer.

While meta-analyses such as this one have their own limitations, the results reported here make it unlikely that any of the five polymorphisms convey a substantially enhanced lung cancer risk in the general population. This does not exclude the possibility that other alleles in the four genes examined here, alleles in other GST genes, or combinations of GST alleles do exert substantial influences on an individual's lung cancer risk. As the authors conclude, the chances for discovering such links in future studies are likely much higher if such studies are large and carefully designed.

Tumor diameter - an important prognostic indicator for curability

Wed, 15 Feb 2006 14:54:37 PST

( from http://www.rxpgnews.com ) Smaller tumors in the lungs appear to be less likely to have spread than larger tumors among patients with asymptomatic lung cancer, suggesting that early screening may be useful in detecting cancers that are still curable, according to a new article in the February 13 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Cancers in the earliest stage, which have not yet spread beyond the lungs, are divided by size into stage IA (tumors less than 30 millimeters in diameter) and stage IB (tumors larger than 30 millimeters in diameter), according to background information in the article. The development of computed tomography (CT) scanning has allowed physicians to detect lung tumors at a smaller size, prompting some to call for more subdivisions of stage I cancers. Though tumor size has been linked to cancer prognosis in patients with symptoms, the relationship between tumor size, metastasis (cancer spread) and prognosis in asymptomatic individuals has been unclear, the authors write.

Claudia I. Henschke, M.D., Ph.D., New York Presbyterian Hospital-Weill Cornell Medical Center, New York, and colleagues from the International Early Lung Cancer Action Program screened 28,689 men and women for lung cancer at 38 institutions worldwide between 1993 and 2004. Four hundred sixty-four patients were diagnosed with lung cancer as the result of the screening. The researchers classified the participants' lung cancers based on their type-small cell or non-small cell-as well as the size (diameter) of their tumors at diagnosis and whether or not they had metastasized. They also recorded the consistency of the tumors as solid, nonsolid or part-solid.

For the 436 patients with non-small cell cancers, which are less aggressive than small-cell cancers, the likelihood of metastasis increased along with tumor size. When the researchers analyzed the tumors by consistency, they found the association strongest for solid tumors, weaker for part-solid tumors and not apparent for nonsolid tumors. For the few (28) cases of small cell cancer, the relationship appeared strong for those tumors as well. The percentages of nonmetastasized cancer of all types were much higher than those reported in previous studies.

"The pattern confirmed herein suggests the usefulness of finding latent cancers at small sizes," the authors conclude. "Most lung cancers without evidence of lymph node metastases are curable, with the curability rate being higher at smaller sizes. This suggests that tumor diameter also serves as a prognostic indicator for curability, perhaps even for micrometastases not detectable by our current techniques."

Palliative radiation can cure some NSCLC

Mon, 23 Jan 2006 16:07:37 PST

( from http://www.rxpgnews.com ) About one in a hundred patients with apparently incurable non-small cell lung cancer (NSCLC) survive five or more years after being given relatively small doses of radiation therapy (RT) meant to ease symptoms, according to a new study. Published in the March 1, 2006 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the study says a new subset of patients with NSCLC appears to have disease that is curable with minimal therapy, and may explain occasional cures attributed to unconventional therapies or faith healing.

NSCLC is by far the most common type of lung cancer. With an overall five year survival of only 40 percent, it is also one of the deadliest. If caught early, five year survival can reach 60 percent. Five year survival in farther advanced disease is approximately 15 percent.

Patients who are diagnosed with disease that is too advanced for curative treatment remain eligible for palliative therapies intended to provide symptom relief, including comparatively low doses of localized RT. Physicians have long made clinical observations that some patients receiving palliative RT long outlive their estimated survival and a few report even cures. Given that therapeutic doses of RT are much higher, it is not surprising that these reports require evidence-based confirmation.

Michael Mac Manus, M.D., a radiation oncologist at the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues clinically followed 2337 confirmed and apparently incurable NSCLC patients who had received palliative dose RT.

Approximately 1.1 percent of the 2337 survived five or more years, including 18 who achieved an apparent cure. Although five year survivors were more likely to have higher functional scores at diagnosis and less likely to have metastatic disease compared to patients who lived less than five years, there were no other conventional prognostic factors to predict survival with palliative-dosed RT.

"Our data," conclude the researchers "show that close to 1 percent of patients with NSCLC have prolonged survival with doses of palliative RT that would not normally be considered sufficient for long term disease control." Future studies should focus on identifying patient characteristics because "prospective identification of such patients could potentially profoundly influence treatment."

Bexarotene shows promise in lung cancer treatment

Wed, 18 Jan 2006 17:51:37 PST

( from http://www.rxpgnews.com ) The ideal substance to prevent cancer would block tumor growth without causing unpleasant or dangerous side effects. Researchers at Washington University School of Medicine in St. Louis now report that a compound related to vitamin A shows promise in preventing or slowing tumor growth in mice prone to lung cancer. The compound, called bexarotene, doesn't cause the severe skin irritations that have limited the use of other vitamin A derivatives in cancer therapies.

"In the cancer prevention field, you look for drugs that can be given to healthy patients who have a higher risk of developing cancer," says Ming You, M.D., Ph.D., director of the Chemoprevention Program at the Siteman Cancer Center. "These patients wouldn't want to take a medication that makes them feel sick when they don't have cancer. So the drugs should be very well-tolerated and not cause harmful side effects."

In other studies, bexarotene showed some promise in cancer treatment. It extended survival in patients with non-small cell lung cancer, the most common type of lung cancer and one that has a five-year survival rate of less than 5 percent when diagnosed at the advanced stage.

In the current study, due to appear in an upcoming issue of Oncogene, Yian Wang, M.D., Ph.D., associate professor of surgery, You, professor of surgery, and colleagues demonstrate that lung-cancer-susceptible mice receiving non-toxic doses of bexarotene ended up with fewer and smaller benign and malignant tumors than mice that were not treated with bexarotene. The researchers saw a reduction of almost 50 percent in terms of total tumor burden in mice who were given bexarotene for 12 weeks after the animals had already developed benign tumors following injection of a lung carcinogen. Bexarotene also inhibited the progression of benign to malignant tumors by about 50 percent. The mice were engineered to have the genetic alterations seen in human lung cancers, so they readily develop lung cancer when given known lung carcinogens.

"Seeing this magnitude of response in such a strongly susceptible mouse suggests bexarotene is a potentially viable lung cancer prevention candidate," You says.

Vitamin A analogs called retinoids have been studied for several years as potential chemotherapeutic agents because they help regulate cell division, growth, differentiation and proliferation. A new class of these vitamin A relatives has been created that includes bexarotene. These substances are called the rexinoids, so named because they are attracted to a molecule on cell surfaces called RXR.

Rexinoids tend to be much less toxic than retinoids, and among them bexarotene has so far shown the most promise as a chemopreventive medicine. However, although it causes far fewer side effects, bexarotene does have the effect of increasing blood lipid levels in many patients. Patients taking bexarotene often need to take a drug to lower their cholesterol and triglyceride levels.

A new rexinoid called UAB30, just becoming available for laboratory studies, seems to have the potential to reduce even the high-lipid side effect.

"We will be testing this new compound, too, and if it turns out to be effective, these rexinoids will most likely become candidates for clinical trials in patients with precancerous nodules or bronchial dysplasia," You says. "If the trials show reduction of cancers, I think these drugs may well become routinely used for lung cancer prevention." Prevention is considered vital to decreasing the impact of lung cancer, which accounts for 32 percent of cancer deaths in men and 25 percent of cancer deaths in women. The majority of lung cancer patients are not diagnosed until their cancer has reached an advanced stage, and current treatment regimens do not substantially improve the outcome for most of these patients.

"Advanced or metastatic cancer is sort of a genius at adapting," You says. "By that point, the cancer cells that have survived have overcome so many obstacles and gained so many abilities that they are difficult to kill. They have a very unstable genome that can change quickly to resist the treatments we use. It's best if you attack cancer in its infancy or at the precancerous stage. The earlier the better."

Aromatase inhibitors may slow growth of lung cancer as well

Thu, 15 Dec 2005 15:47:38 PST

( from http://www.rxpgnews.com ) A medical student conducting research on a Howard Hughes Medical Institute (HHMI) fellowship and colleagues have managed to stop the growth of human lung cancer cells in mice with a class of breast cancer drugs called aromatase inhibitors.

The studies are reported in the December 15, 2005 issue of the journal Cancer Research. It was a natural progression of the work that had already been done linking estrogen and lung cancer, said Olga Weinberg, who delayed her fourth year at Vanderbilt University School of Medicine to work on the project.

The findings suggest a new way to treat lung cancer in women - a group whose death rate from the disease is surging.

More women are dying now from lung cancer than from breast cancer, said senior author Richard Pietras, Weinberg's research mentor at the University of California at Los Angeles. To see if they could block this growth, the team started with the enzyme aromatase. It presented a natural target because aromatase converts testosterone into estradiol, a potent form of estrogen also used in hormone replacement therapy. In addition, drugs that inhibit aromatase have already made it to market as new treatments for breast cancer.

The production of estrogen takes several steps, and aromatase is the key to the process, said Weinberg. Without aromatase, you don't get estrogen.

To confirm that lung cancer needs aromatase, the team first searched for the enzyme in laboratory-grown lung cancer cells. After finding it there, they also searched 53 non-small cell lung tumor samples from patients Using an antibody specific for aromatase and immunohistochemistry techniques, they found that 88 percent of the specimens from women and 86 percent from men contained high levels of the enzyme.

The team proceeded to highlight actual aromatase activity with a radioactive tracer, finding the enzyme active in both the laboratory cells and the frozen specimens. They double-checked by depleting the cells of estrogen, then feeding them testosterone: If aromatase was at work, the cells would produce estrogen. The team treated their cells with the drug anastrozole for 48 hours, finding that it did in fact shut down aromatase activity and retard tumor growth in the lab.

We found that tumors with both high and low levels of aromatase were sensitive to the drug, said Pietras.

Finally, the team grafted human lung tumors onto mice. The tumors in the mice taking the drug grew 90 percent slower than the tumors in the untreated mice.

HHMI awards medical student research fellowships to enable medical students to spend a year during their medical training doing research. As Weinberg finishes her medical degree at Vanderbilt University School of Medicine this year, Pietras and colleagues at UCLA have begun testing several other aromatase inhibitors against lung cancer. They hope to progress to human clinical trials, which should progress quickly since the drugs already have FDA approval.

Women with Lung Cancer Live Longer than Men

Fri, 04 Nov 2005 22:00:38 PST

( from http://www.rxpgnews.com ) Women with lung cancer are living longer than men, even when the disease is untreated. A new study presented at CHEST 2005, the 71st annual international scientific assembly of the of Chest Physicians (ACCP), found that in patients receiving treatment for lung cancer, women had significantly better survival rates than men. However, in untreated patients, women also had a 21 percent decreased risk of death as compared with men, leading researchers to believe lung cancer in women has a different biologic behavior and natural history than in men.

"In patients with lung cancer receiving treatment, women have shown a better response to therapy, resulting in better survival rates," said Juan Wisnivesky, MD, MPH, FCCP, Mount Sinai School of Medicine, New York, NY. "Yet, new data suggest that even in untreated patients, women with lung cancer still live longer than men, despite the presence of other medical conditions or gender differences in life expectancy. This suggests that the progression of lung cancer has a biological basis, with the disease being more aggressive in men than women."

Researchers from Mount Sinai School of Medicine reviewed 18,967 cases of stage I and II non-small cell lung cancer diagnosed between 1991 and 1999 from the Surveillance, Epidemiology, and End Results registry linked to Medicare records. Patients were grouped into three categories according to treatment received: surgery, radiation or chemotherapy, and untreated cases. After adjusting for comorbidities and general life expectancy, researchers found that women in the three groups had significantly better cancer specific, overall, and relative survival than men. In treated patients, lung cancer specific 5-year survival for women was 54 percent compared with 40 percent for men and women had a 30 percent decreased risk of death compared with men. Among untreated patients, women had a 21 percent decreased risk of lung cancer deaths after adjusting for differences in age, race, socioeconomic status, access to care, and cancer histology. Researchers also found that women lived longer than men after controlling for age, race, disease stage at diagnosis, histology, median income, geographic area, access to care, and type of treatment.

"It is clear that gender plays a role in the survival rate of men and women," said W. Michael Alberts, MD, FCCP, President of the of Chest Physicians. "Physicians caring for patients with lung cancer should consider the inherent progression of lung cancer among men and women when deciding on a patient's course of treatment."

Epidermal Growth Factor Receptor (EGFR) Mutations and Lung Cancer

Fri, 07 Oct 2005 18:55:38 PST

( from http://www.rxpgnews.com ) Tyrosine kinases of the epidermal growth factor receptor (EGFR) family are frequently mutated in human cancers. Mutations in the tyrosine kinase domain of EGFR (encoded by exons 18â24) have mostly been found in lung cancers. Some, but not all, lung cancers carrying such mutations are responsive to treatment with small-molecule EGFR inhibitors, including the two FDA-approved drugs erlotinib and gefitinib.

Matthew Meyerson and colleagues undertook a systematic study of the different classes of EGFR mutations found in lung cancers in order to understand their roles in tumorigenesis on one hand, and their relation to drug sensitivity on the other. They introduced different altered EGFR versions into fibroblast and lung epithelial cells, and found that all of the mutant proteins transformed both cell types in an EGF-independent manner. Transformation was associated with constitutive kinase activity and with the activation of known downstream signaling pathways.

While the various mutant receptors had similar transforming capabilities, cells expressing them differed in their response to EGFR inhibitors. Transformation of cells expressing mutations in exons 18, 19, and 21 was inhibited by 100 nM erlotinib or gefitinib, whereas no significant inhibitory effect on cells expressing an exon 20 insertion mutation was seen even at much higher concentrations of either drug. This result is consistent with the lack of clinical responses to erlotinib or gefitinib in three lung cancer patients with exon 20 mutations. In contrast, when the researchers tested another experimental EGFR inhibitor called CL-387,785, they found cells expressing the exon 20 insertion mutation to be sensitive, consistent with previous studies that had found similar patterns with other EGFR exon 20 mutations.

These results highlight the problems and the possibilities of individualized cancer therapy. One drug is unlikely to fit all tumors, not even all tumors with mutations in a specific oncogene. On the other hand, having a collection of drugs against a particular target increases chances that one of them will prove effective, and that alternatives exist when tumors develop resistance. Developing such a collection and selecting the right drug for the right patient is a challenge not only scientifically but also economically.

Number of Cigarettes Determine Extent of Lung Cancer Risk

Wed, 28 Sep 2005 13:42:38 PST

( from http://www.rxpgnews.com ) Heavy smokers (more than 15 cigarettes per day) can reduce their risk of lung cancer if they decrease smoking by 50 percent, according to a study in the September 28 issue of JAMA.
Lung cancer remains the leading cause of cancer death worldwide, and an estimated 90 percent of lung cancer cases are tobacco-related, according to background information in the article. Despite efforts to prevent people from beginning smoking and to encourage smoking cessation, the overall prevalence of cigarette smoking is still high and many smokers are unable or unwilling to completely quit.
Participants were divided into six groups, according to smoking habits: continued heavy smokers (15 or more cigarettes per day), reducers (reduced from 15 or more cigarettes per day by a minimum of 50 percent without quitting), continued light smokers (one to 14 cigarettes per day), quitters (stopped between first and second examination), stable ex-smokers, and never smokers. During follow-up, 864 participants were diagnosed with lung cancer. There were 360 lung cancer cases among women and 504 cases among men.
"Reducing tobacco consumption from approximately 20 cigarettes per day to less than ten was associated with a 27 percent reduction in lung cancer risk compared with unchanged heavy smoking," the authors report.
"Participants who were continued light smokers or who quit smoking between baseline and follow-up reduced their lung cancer risk by 56 percent and 50 percent, respectively, compared with persistent heavy smokers," they continue. "Risk of lung cancer among the stable ex-smokers was 83 percent lower than among the heavy smokers, but still significantly higher than among the never smokers."
The authors point out that their study results indicate risk reduction is disproportionately smaller than the corresponding smoking reduction. "More data from long-term studies of smoking reduction are warranted, but for the present, smoking cessation and not smoking reduction should still be advocated as the ultimate method of reducing harm from smoking, especially since diseases such as COPD [chronic obstructive pulmonary disease] and [heart attack], which have a larger public health effect than lung cancer, have not shown any reductions in risks after smoking reduction," the authors conclude.

In an accompanying editorial, Lawrence J. Dacey, M.D., M.S., and David W. Johnstone, M.D., of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., write that it is important to inform patients who smoke that the more they can reduce the number of cigarettes they smoke, the more they will decrease their risk of lung cancer.

"Physicians and other health professionals should do all they can to help their patients who smoke reduce their risk of getting lung cancer. Total discontinuation of smoking, no matter the age of the patient, will provide the greatest benefit," they write. "The most effective interventions to achieve permanent smoking cessation combine pharmacological therapy and referral for intensive behavioral support from a trained counselor. Those patients who cannot quit smoking despite all efforts should be strongly encouraged to cut down on their cigarette consumption as much as possible, since doing so will significantly decrease their risk of lung cancer."

Dietary Phytoestrogens Reduce Risk of Lung Cancer

Wed, 28 Sep 2005 13:31:38 PST

( from http://www.rxpgnews.com ) A diet higher in plant-derived compounds known as phytoestrogens is linked with a lower lung cancer risk, according to a study in the September 28 issue of JAMA.

Phytoestrogens are plant-derived nonsteroidal compounds found in soy products, grains, carrots, spinach, broccoli, and other fruits and vegetables, according to background information in the article. Phytoestrogens have been shown to have a protective effect against some solid tumors, but there has been little epidemiologic research focused on dietary intake of phytoestrogens and lung cancer risk.

Matthew B. Schabath, Ph.D., and colleagues at the University of Texas M.D. Anderson Cancer Center, Houston, analyzed data from an ongoing case-control study to examine the relationship between dietary intake of phytoestrogens and the risk of lung cancer. The study included 1,674 patients with lung cancer (cases) and 1,735 matched healthy controls. From July 1995 through October 2003, study participants were personally interviewed to obtain information on demographics, socioeconomics, and smoking history. A food frequency questionnaire was used to collect dietary data on intake of 12 individual phytoestrogens.

Reduction in lung cancer risk tended to increase with increasing phytoestrogen intake. "The highest quartiles of total phytosterols, isoflavones, lignans, and phytoestrogens were each associated with reductions in risk of lung cancer ranging from 21 percent for phytosterols to 46 percent for total phytoestrogens from food sources only," the authors write.

"For men, statistically significant trends for decreasing risk with increasing intake were noted for each phytoestrogen group, with protective effects for the highest quartile of intake ranging from 24 percent for phytosterols to 44 percent for isoflavones, while in women, significant trends were only present for intake of total phytoestrogens from food sources only, with a 34 percent protective effect for the highest quartile of intake," the authors report.

The apparent benefits of high phytoestrogen intake were evident in both current smokers and those who had never smoked, but less apparent in former smokers.

In women, statistically significant joint effects were evident between hormone therapy use and phytoestrogen intake. "Specifically, high intake of the lignans [metabolites] enterolactone and enterodiol and use of hormone therapy were associated with a 50 percent reduction in risk of lung cancer," the authors report.

"In summary, these data provide further support for the limited but growing epidemiologic evidence that estrogens and phytoestrogens are associated with a decrease in risk of lung cancer, especially in never and current smokers," they conclude.

In an accompanying editorial, Lawrence J. Dacey, M.D., M.S., and David W. Johnstone, M.D., of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., urge physicians and other health professionals to talk with their patients about the importance of diet in cancer prevention.

"...patients should be informed that they may further reduce their risk of developing cancer by adopting a diet rich in fruits and vegetables," they write. "Clinicians who actively and aggressively educate their patients and follow up on their efforts to modify their cancer risks will help lessen the great personal suffering and societal burden inflicted by lung cancer."

PGT202 trial demonstrated survival advantage with paclitaxel poliglumex

Wed, 28 Sep 2005 13:00:38 PST

( from http://www.rxpgnews.com ) According to the American Cancer Society, lung cancer is the leading cause of cancer death among both men and women and results in more deaths per year than colorectal, breast, prostate, liver, and kidney cancers combined. Nearly 60 percent of people with lung cancer die within one year of their diagnosis and nearly 75 percent die within 2 years; figures which have not improved in 10 years. Lung cancer is expected to kill nearly twice as many women as breast cancer this year.

At a presentation at the UBS Global Life Sciences Conference, Cell Therapeutics, Inc. (CTI) (Nasdaq: CTIC; MTAX: CTIC) presented new results from a recently completed phase II clinical trial of XYOTAX in the first-line treatment of men and women with advanced non-small cell lung cancer (NSCLC).

In that single arm study, known as PGT202, the 35 women who received XYOTAX plus carboplatin had a 36 percent probability of living at least 1 year compared to only 16 percent in the 39 men receiving the same regimen. A pooled analysis of XYOTAX treated patients from STELLAR 3, STELLAR 4 and the PGT202 trial demonstrated a statistically significant (p=0.004) survival advantage for women treated when compared to men, with women having a 39 percent probability of surviving at least 1 year compared to 25 percent of men (HR =1.37, log rank p = 0.014 N = 463 patients). The Company previously reported that in a combined analysis of STELLAR 3 and 4, women treated with XYOTAX survived significantly longer than women treated on the standard chemotherapy control arms of these studies.

"To the best of our knowledge this is the first time a drug therapy for advanced lung cancer has consistently demonstrated such a strong survival advantage for women compared to men or compared to women randomized to treatment with standard chemotherapy," noted Jack W. Singer, M.D., Chief Medical Officer at CTI. "We are currently evaluating the effect of estrogen on the metabolism of XYOTAX in normal and cancerous tissues to provide mechanistic support for these important clinical results."

In August, CTI outlined its plans to file a New Drug Application (NDA) in the United States and a Marketing Authorization Application (MAA) in Europe in 2006 based on the results of its Stellar 3 and 4 trials.

Several studies have indicated that compared to men, women who smoke are more likely to develop lung cancer at a younger age and at lower levels of exposure to cigarette smoke. Non-smoking women are at higher risk for developing lung cancer than non-smoking men. Research has focused on the influence of genetic differences between men and women and on the role of estrogen to explain these findings. Estrogen enhances the effects of carcinogens in the environment and in smoke, possibly leading to a higher risk for NSCLC and once it occurs, appears to enhance its development. Since women have higher levels of estrogen than men, and younger women have higher levels of estrogen than older women, this may in part be responsible for their higher risk for NSCLC. Developing therapies that are favorably influenced by estrogen may provide a gender-targeted therapeutic approach to the treatment of NSCLC.

Epigenetic Activity Silences Rb2/P130 Gene In Lung Cancer

Wed, 14 Sep 2005 02:19:38 PST

( from http://www.rxpgnews.com ) The attaching of methyl--or chemical--groups onto DNA sequences within the tumor suppressing gene Rb2/p130 can cause the gene to cease functioning in non-small lung cancer cells (NSLC) and retinoblastoma cells, researchers at Temple University's Sbarro Institute for Cancer Research and Molecular Medicine and Italy's University of Siena have discovered.

Their findings are reported in two studies: "Tumor-specific exon 1 mutations could be the 'hit event' predisposing Rb2/p130 gene to epigenetic silencing in lung cancer" and "Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach," both of which appear in September issues of Oncogene (www.nature.com/onc).

The joint studies at Temple and Siena were coordinated by Antonio Giordano, M.D., Ph.D., director of Sbarro Institute at Temple (www.shro.org), and by Marcella Macaluso of the Sbarro Institute and Caterina Cinti of both Centro Nazionale Ricerche and the University of Siena.

Giordano said that the researchers were puzzled when they found Rb2/130, the tumor suppressing gene discovered by Giordano in the early 1990s, in an epigenetic state in both the NSLC and retinoblastoma cells. In this epigenetic state, the gene showed no signs of mutation, but is silent in its expression or function.

Further examination of the gene found that it had been methylated, a process in which methyl or chemical groups attached themselves to the gene, attacking a sequence of the Rb2/p130's DNA and thus causing it to cease functioning.

"These studies are providing very important information on how cancerous and pre-cancerous conditions can be detected by the presence of the methylated state of Rb2/p130," said Giordano. "These cancerous or pre-cancerous conditions can be treated with drugs or agents that de-methylate the Rb2/p130 gene. Once the drugs or agents disconnect the methyl groups from Rb2/p130, the gene begins to again express itself or function normally."

He likened this methylation/de-methylation phenomenon--which can stop or start the expression of a gene--to a lightswitch which is used to turn a lamp off or on.

Giordano said some of these agents that will de-methylate Rb2 are already available, but have not been previously used because researchers did not know that the lack of expression from the gene was being caused by its methylation.

"Our discovery is providing a smart method to identify novel methylated drugs or agents that can assist in restarting the vital expression of Rb2/p130," he said.

Through the use of a simple genetic (both at DNA and Protein level) test of Rb2 gene and protein from a human tissue sample, said Giordano, scientists could determine if cancerous or pre-cancerous conditions exist because of the epigenetic state of the gene.

"We could develop a potential test which could save many, many people from the ravages of cancer," he said.

Better Combination Therapy for Patients with Locally Advanced Lung Cancer

Sun, 04 Sep 2005 07:59:38 PST

( from http://www.rxpgnews.com ) While researchers have learned in the last decade that combining chemotherapy with radiation is better than radiation alone for treating non-small cell lung cancer patients with locally advanced disease cancer confined to the lungs finding the right combination of drugs and the best timing of treatment has been tricky.

A new study led by lung cancer specialists at Jefferson Medical College adds to growing evidence that giving patients both chemotherapy and radiation in the beginning of treatment may help patients live longer. Non-small-cell lung cancer accounts for about 80 percent of all cases of lung cancer. An estimated 40,000 Americans are diagnosed each year with locally advanced disease.

This is a further step in looking at what is the best combination of two chemotherapy agents with radiation, which will enable us to move forward and study it more systematically, says Walter J. Curran Jr., M.D., professor and chair of radiation oncology at Jefferson Medical College at Thomas Jefferson University in Philadelphia and clinical director of Jeffersons Kimmel Cancer Center, who led the research.

There are new biologic agents we want to test with chemotherapy, with radiation and with both, he notes. Finding the best combination of chemotherapy and radiation provides a template by which we can test these agents.

The results appear September 1, 2005 in the Journal of Clinical Oncology.

In the multicenter, randomized phase 2 trial, researchers compared three different approaches to treating inoperable non-small-cell lung cancer that had not spread beyond the lungs. They divided more than 250 patients into three treatment arms. One group received chemotherapy before radiation. A second group had chemotherapy before and during radiation. Patients in the third arm received chemotherapy and radiation at the same time, then added a little more chemotherapy after. Each arm had the same schedule of radiation and were given the same two standard chemotherapy agents, carboplatin and paclitaxel.

Dr. Curran and his colleagues found that the patients in the third arm did best, living several months more on average when compared against the standard treatment.

Thats in keeping with the observed results of other studies, Dr. Curran says. Giving radiation and chemotherapy from day one appears to be the best approach for these patients, though side effects can at first appear to be worse.

Researchers are already looking at targeted agents such as bevacizumab, cetuximab and other agents with chemotherapy and radiation in lung cancer, he says. This kind of study will help guide us as to which schedule to use.

Some other institutions that participated in the trial include medical centers at the University of Pittsburgh and Vanderbilt University and Rush University Medical Center.

Diagnostic Strategy May Help Determine Stage Of Lung Cancer More Accurately

Wed, 24 Aug 2005 19:29:38 PST

( from http://www.rxpgnews.com ) A preoperative testing strategy combining two procedures may help improve the accuracy of determining the stage of lung cancer, according to an article in the August 24/31 issue of JAMA.

Up to 40 percent of thoracotomies (surgical incision of the chest wall often involving surgery of the lung) performed for non-small cell lung cancer (NSCLC) are reported to be unnecessary, predominantly due to inaccurate preoperative detection of lymph node metastases, according to background information in the article. Accurate preoperative staging is important in identifying those patients who will benefit from surgical resection (removal of tissue). Currently available staging techniques have limited accuracy in selecting those lung cancer patients without regional lymph node metastases.

Transesophageal ultrasound-guided fine needle aspiration (removal of cells or tissue through a needle) (EUS-FNA) is a minimally invasive and safe technique than can target different lymph node stations and is complementary to mediastinoscopy (examination of the mediastinum [a part of the middle of the thoracic cavity] using a special scope that is inserted through an incision above the sternum) in its diagnostic reach. With EUS-FNA, an ultrasound transducer (a transmitter and receiver of ultrasound information) incorporated on top of an endoscope enables the investigator to visualize and insert the aspiration needle into mediastinal lymph nodes under real-time ultrasound guidance. The EUS-FNA examination has a sensitivity of 88 percent and a specificity of 91 percent in analyzing mediastinal lymph nodes. To date it is not known how EUS-FNA compares with mediastinoscopy, nor to what extent the combination of EUS-FNA and mediastinoscopy improves preoperative staging.

Jouke T. Annema, M.D., Ph.D., of Leiden University Medical Center, Leiden, the Netherlands, and colleagues conducted a study to determine whether lung cancer staging by EUS-FNA in addition to mediastinoscopy improved preoperative staging compared with staging by mediastinoscopy alone. During a 3-year period (2000-2003), 107 patients with potential resectable non-small cell lung cancer underwent preoperative staging by both EUS-FNA and mediastinoscopy. Patients underwent thoracotomy with tumor resection if mediastinoscopy was negative. Surgical-pathological staging was compared with preoperative findings and the added benefit of the combined strategy was assessed. The multicenter study was performed in 1 referral and 5 general hospitals in the Netherlands.

The researchers found that the combination of EUS-FNA and mediastinoscopy identified more patients with tumor invasion or lymph node metastases (36 percent) compared with either mediastinoscopy alone (20 percent) or EUS-FNA (28 percent) alone. This indicated that 16 percent of thoractomies could have been avoided by using EUS-FNA in addition to mediastinoscopy. However, 2 percent of the EUS-FNA findings were false-positive.

"The results can be explained by the fact that EUS-FNA and mediastinoscopy have a complementary reach in assessing regional lymph node stations and in the ability of EUS-FNA to detect mediastinal tumor invasion," the authors write. "Our findings are directly applicable to clinical practice."

"Overall, mediastinoscopy and EUS-FNA have inherent limitations and they should be viewed as complementary in the regional staging of NSCLC. These preliminary findings suggest that EUS-FNA, a novel, minimally invasive staging procedure for lung cancer, may improve the preoperative staging due to the complementary reach of EUS-FNA in detecting mediastinal lymph node metastases and the ability to assess mediastinal tumor invasion. However, the occurrence of false-positive EUS-FNA findings in selected cases needs to be further investigated," the researchers conclude.

Nimotuzumab Approved for Non-Small-Cell Lung Cancer Trial

Thu, 18 Aug 2005 11:55:38 PST

( from http://www.rxpgnews.com ) YM BioSciences Inc. , the cancer product development company, today announced that Health Canada has cleared a Clinical Trial Application (CTA) for a multi-center Phase I/II trial utilizing YM's anti-EGFr monoclonal antibody, nimotuzumab (TheraCIM). The randomized Non-Small-Cell Lung Cancer (NSCLC) trial will compare the effects of the combination of nimotuzumab with radiation against radiation alone in patients with stage IIB and III disease who are found to be insufficiently fit to tolerate the standard-of-care or who are not amenable to treatment with curative intent.

"YM has achieved another milestone by further broadening the clinical development program for nimotuzumab. We expect that the population of essentially untreatable patients with NSCLC, whose only option is to be treated palliatively with radiation, will benefit from the addition of our antibody to this treatment modality," said David Allan, Chairman and CEO of YM. "Together with our European development partner, Oncoscience AG, we have identified numerous important tumour targets where we expect nimotuzumab could benefit patients. In particular, nimotuzumab has demonstrated very encouraging results in both children and adults with brain cancer, and we anticipate being able to further demonstrate this benefit in planned pivotal Phase III trials. The drug is also currently undergoing a Phase II monotherapy trial in Europe in patients with advanced metastatic pancreatic cancer."

The NSCLC trial will be initiated in Canada and extended to Korea, where YM partner Kuhnil Pharmaceutical Co. will fund the development of nimotuzumab for this territory. The trial is expected to enroll approximately 100 patients in total and complete recruitment in approximately 20 months with the prospect of a final report before the end of 2007. The endpoint of the Phase II trial is an increase in local tumor control.

"The entire class of EGFr-targeting agents has clearly and clinically demonstrated its ability to enhance the effect of radiation," said Dr. Paul Keane, Director of Medical Affairs at YM. "A randomized trial with nimotuzumab that included 130 patients suffering from nasopharyngeal cancer was recently completed in China and demonstrated the substantial benefit of nimotuzumab when added to standard radiation therapy, resulting in the drug being approved for sale in China. Nimotuzumab has shown clinical benefit as a monotherapy as well and is unique in its class because it has not produced the emotionally and physically debilitating side effects of rash or severe diarrhea suffered by patients treated with the other drugs in this class."

Nimotuzumab is licensed to YM's subsidiary CIMYM Inc. by CIMAB S.A., a corporation representing the Center of Molecular Immunology in Havana. CIMYM's licenses are for the major market countries including Europe, North America and the Pacific Rim countries excluding China. CIMAB has separate licenses in India with Biocon Biopharmaceuticals Limited and the People's Republic of China with Biotech Pharmaceuticals Limited.

Lung cancer is the leading cause of cancer-related mortality in both men and women. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. Non-small cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers. The standard of care for the treatment of NSCLC is radical therapy utilizing the chemotherapy cisplatin in combination with high dose radiation. Dr. Mark Vincent, staff oncologist at the London Regional Cancer Centre, estimates that the combined population of patients unfit for chemotherapy or unwilling to undergo the treatment because of the often intolerable side effects of chemotherapies may approximate 20% of patients diagnosed with an advanced form of this cancer. In addition, virtually all patients with NSCLC will eventually become refractory to chemotherapy and be treated with radiation as palliative care.

Common lung cancer may begin in newly discovered stem cells

Fri, 17 Jun 2005 03:41:38 PST

( from http://www.rxpgnews.com ) The most common form of lung cancer may begin in a group of newly isolated lung stem cells, according to researchers from the Howard Hughes Medical Institute.

Working in a mouse model, the researchers isolated a novel type of lung cell that can divide into fresh copies of itself and into the two more specialized kinds of cells deep in the lung. Their experiments show that at the earliest stage of tumor development, the stem cell appears to be the first lung cells that respond to a cancer-causing mutation. The newly identified cell type fulfills all but one of the strictest criteria that scientists look for in defining adult stem cells.

The study is published in the June 17, 2005, issue of the journal Cell.

"The work of Bender Kim and colleagues represents not only a leap forward in our understanding of lung tumorigenesis, it also heralds the arrival of a valuable mouse model for identifying those cells that should be the targets of therapeutic intervention," wrote Anton Berns of The Netherlands Cancer Center in Amsterdam in an accompanying commentary in Cell.

The identification of the cells could lead to earlier diagnosis of lung cancer in people. Lung cancer is the leading cause of cancer-related death in the United States, in part because it is usually detected at an advanced stage. Patients in whom the disease has spread to other organs have a five-year survival rate of only two percent. In contrast, lung cancer detected at an early stage boasts a 50 percent survival rate over a five-year period.

"There are many similarities between stem cells and cancer," said first author Carla Bender Kim, a postdoctoral fellow in the lab of senior author Tyler Jacks, a Howard Hughes Medical Institute investigator at Massachusetts Institute of Technology. "Cancer cells can continue to divide many times. Likewise, stem cells can divide over the lifespan of the organism. Also, tumors are very heterogeneous, composed of many different cells, and stem cells can give rise to different types of cells."

The researchers do not know if the stem cells play a role in more established tumors, but other scientists have found evidence that some human cancers contain a small but virulent group of cells known as "cancer stem cells" that regenerate the tumor, a capacity that most cells in a tumor lack.

"They may be the cells that we have to eliminate in cancer in order to obtain durable cures for the disease," said Jacks. "Along the way, we need to know how these cancer stem cells become different from normal stem cells."

Bender Kim started with a mouse model of non-small cell adenocarcinoma recently developed by another postdoc and graduate student in Jacks's lab to study the progression of lung cancer and the effects of conventional and experimental therapies.

The mouse carries a silent genetic mutation of an oncogene known as K-ras, which is found in about one-third of all tested non-small cell lung cancers in people. A specially designed virus can activate the mutation in only a few cells. The mouse is known as a conditional mutant strain. In this case, the mouse inhales a small amount of virus that activates the K-ras oncogene in some of the lung cells.

Four years ago, Jacks's lab reported that some of the resulting cancer cells carry the molecular markers of both of the two kinds of cells found in non-small lung cell cancers. In mice, the tumors start deep in the lung, past the trachea and the branches to the lobes. Ciliated cells that catch debris give way to the bronchiolar cells called Clara cells. The airways end with the alveolar cells, which are the grape-cluster-like sacks lined with microscopic vessels, where oxygen and carbon dioxide are exchanged.

At the junction of the bronchioles and alveoli, other groups have found evidence of cells that are resistant to damage and are involved in repair and maintenance of tissue. They have proposed that these junctions might be a stem cell niche.

Bender Kim and her co-authors first isolated the stem cells, which they named bronchioalveolar stem cells (BASCs), from the earliest stage of the mouse tumors. Then, she purified them from the lungs of healthy mice. On the surface of BASCs, Bender Kim found another protein marker that is also present on the surface of better-studied hematopoietic stem cells. She made certain that BASCs were not stem cells of the blood or blood vessels.

The BASCs passed the rigorous tests for stem cells. In response to two types of lung damage that killed the more specialized cells, BASCs proliferated and appeared to give rise to the Clara or alveolar cells lining the airways. In tissue cultures of normal mouse cells, only the BASCs could grow more of themselves or differentiate into Clara or alveolar cells. In tissue cultures of the mutant mouse lung cells, the activated oncogene only triggered growth of the BASCs, not of the more specialized alveolar cells.

"The stem cells may retain mutations from the same damage that kills the more specialized cells," Bender Kim speculates. "If the DNA is not repaired properly, and if the mutation happens to affect a tumor suppressor gene or oncogene, it could start the process of forming a tumor. There are certainly suggestions that various tumors might arise in locations where there has been a previous injury."

The researchers acknowledge that the ultimate stem cell test remains. "One thing we have not done is taken BASCs and put them back into the mouse and show in vivo that they perform as stem cells," Bender Kim said. "We don't have an assay for that yet."

With hematopoietic stem cells, for example, scientists can inject the stem cells into the bone marrow of an irradiated mouse and replace the entire blood system, the basis of bone marrow transplantation. Solid tissue is trickier. Bender Kim and her colleagues do not yet know the optimal microenvironment for stem cells of the lung, including the roles of the neighboring cells that support the stem cells and specialized lung cells. Still, she says their studies are as rigorous as the generally accepted reports of stem cells found in the skin, brain, testes and gut.

The lab has already teamed up with another research group to develop microscopic fluorescent probes to image the unique molecular surface of BASCs and track the progress of the naturally arising tumor, Jacks said. The similar genetic activity profile of mouse tumors with K-ras mutations to the profile of human lung cancer samples make the researchers optimistic about the relevance of targeting BASCs for early tumor detection and chemoprevention in the earliest stage of disease in people.

Discovery of the lung stem cells could lead to new therapies for other lung diseases, such as emphysema and cystic fibrosis. "We tend to emphasize cancer, because we are in a lab that studies cancer," Bender Kim said. "Identifying stem cells is the biggest part of the story. This population could be very useful for more than cancer."

In their paper, the researchers envision more medical possibilities, such as using the adult stem cells to restore defective tissue in incurable fatal chronic lung diseases, such as alveolar cells that are destroyed in emphysema. Or scientists could extract the BASCs, alter their genes, and replace them in a kind of cellular gene therapy for genetic diseases such a cystic fibrosis.

"This work has identified a new population of cells that links the normal biology of the lung to lung cancer development," said Bender Kim. "We need to continue to improve our understanding of how normal cells in the body develop, differentiate, and respond to damage in order to understand the origins of diseases and to develop better ways to treat them."

First Phase III Study to Extend Median Survival Beyond One Year in Advanced Lung Cancer

Sat, 14 May 2005 07:17:38 PST

( from http://www.rxpgnews.com ) Genentech, Inc. (NYSE: DNA) and Roche (SWX Zurich) today announced that data from a Phase III study (E4599) of Avastin (bevacizumab) plus paclitaxel and carboplatin chemotherapies in first-line non-squamous, non-small cell lung cancer (NSCLC) showed the study met its primary efficacy endpoint of improving overall survival. Results from an interim analysis of this study showed that patients receiving Avastin plus paclitaxel and carboplatin had a 30 percent improvement in overall survival (or a hazard ratio of 0.77, which can also be referred to as a 23 percent reduction in the risk of death), compared to patients who received chemotherapy alone. This study showed that median survival of patients treated with Avastin plus chemotherapy was 12.5 months compared to 10.2 months for patients treated with chemotherapy alone.

These data were featured in a press briefing at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). More detailed presentations of the data will be made during a plenary session by Alan B. Sandler, M.D., of Vanderbilt University Medical Center in Nashville (Abstract #LBA4 Saturday, May 14, 5:10 p.m. EDT).

The results of this Phase III study reveal, for the first time, an improvement in survival with the addition of a targeted biologic agent to standard chemotherapy in this patient population, and the first time median survival has been extended beyond one year in advanced lung cancer, said Dr. Sandler. We also observed improvements in other measures of patient benefit, including progression-free survival and tumor response rate.

This study showed a 61 percent improvement in progression-free survival (or a hazard ratio of 0.62, which can also be referred to as a 38 percent reduction in the risk of progression). Median progression-free survival was 6.4 months for patients treated with Avastin plus chemotherapy, compared to 4.5 months for patients treated with chemotherapy alone. The response rate in patients with measurable disease was 27 percent (97/357) in the group receiving Avastin plus chemotherapy, compared to 10 percent (35/350) in the group receiving chemotherapy alone.

In previous clinical experience with Avastin in combination with paclitaxel and carboplatin in NSCLC, patients with a specific type of NSCLC called squamous cell carcinoma had a higher risk of experiencing life-threatening or fatal pulmonary bleeding. These patients were excluded from this Phase III study and the rate of life-threatening or fatal pulmonary bleeding in patients treated with Avastin was substantially reduced from prior clinical studies. A preliminary assessment of adverse events by the investigators showed that Grade 3/4/5 bleeding occurred in 4.5 percent of patients in the Avastin plus chemotherapy arm, compared to 1 percent of patients in the chemotherapy alone arm. Treatment-related deaths occurred at a rate of 2 percent (8/420) in the Avastin plus chemotherapy arm, compared to less than 1 percent (2/427) in the chemotherapy alone arm. Fatal (Grade 5) hemoptysis occurred at a rate of 1 percent (5/420) in the Avastin plus chemotherapy arm.

The preliminary safety assessment showed that the most common adverse events were neutropenia, hypertension and thrombotic events. Grade 3/4 neutropenia occurred in 24 percent of patients treated with Avastin plus chemotherapy and 16 percent of patients who received chemotherapy alone. Hypertension occurred in 6 percent of patients who received Avastin plus chemotherapy and 1 percent of patients who received chemotherapy alone. Grade 3/4 venous thrombosis occurred in 4 percent of patients treated with Avastin plus chemotherapy, compared with 3 percent of patients treated with chemotherapy alone. Grade 3/4 arterial thrombosis occurred in 2 percent of patients treated with Avastin plus chemotherapy, compared with 1 percent in patients treated with chemotherapy alone.

Data from this study show that Avastin may have the potential to become an important new treatment option for patients diagnosed with non-small cell lung cancer, said Hal Barron, M.D., Genentechs senior vice president, development, and chief medical officer. The data from this study are an important advance in lung cancer research and we would like to thank our collaborators at NCI and ECOG for their work on this study, as well as the many patients and their families who made the decision to participate in this study.

Genentech is discussing plans for the filing of a supplemental Biologics License Application (sBLA) for Avastin plus chemotherapy in first-line, advanced NSCLC with the U.S. Food and Drug Administration (FDA).

About the Trial Design
The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), under a Cooperative Research and Development Agreement between NCI and Genentech, Inc., and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG).

This is the first Phase III study to evaluate the therapeutic antibody Avastin in combination with chemotherapy in NSCLC. This was a randomized, controlled, multicenter trial that enrolled 878 patients with previously-untreated advanced NSCLC. The patients enrolled in this trial were randomized to receive treatment with paclitaxel and carboplatin chemotherapies with or without Avastin.

About Avastin
Avastin is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumor angiogenesis and maintenance of existing tumor vessels. By binding to VEGF, Avastin is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis. For full prescribing information, including Boxed Warnings for Avastin and information about Avastin and angiogenesis, visit http://www.gene.com or http://www.avastin.com.

The FDA approved Avastin on February 26, 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy.

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, non-small cell lung and ovarian cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumor cancers and hematologic malignancies. For further information about Avastin clinical trials, please call 888-662-6728.

Avastin Safety Profile
Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.

About VEGF and Tumor Angiogenesis
The link between angiogenesis and cancer growth has been discussed by many researchers for decades. It wasn't until 1989 that a key growth factor influencing the process, VEGF, was discovered by Napoleone Ferrara, M.D., a staff scientist at Genentech. Dr. Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. This research was published in the journal Science in 1989. Dr. Ferrara then created a mouse antibody to this protein. In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumor growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumor growth. Clinical studies with a humanized version of the antibody, Avastin, began in 1997.

About Non-Small Cell Lung Cancer
According to the World Health Organization, there are more than 1.2 million cases worldwide of lung and bronchial cancer each year, causing approximately 1.1 million deaths annually. The drug treated prevalence for non-small cell lung cancer is approximately 175,000 patients, of which an estimated 138,000 patients are stage IIIB/IV. Up to 25 percent of stage IIIB/IV non-small cell lung cancer patients may be ineligible for treatment with Avastin. According to the NCI, lung cancer is the single largest cause of cancer deaths in the United States and is responsible for nearly 30 percent of cancer deaths in this country. NSCLC is the most common form of the disease and accounts for almost 80 percent of all lung cancers.

Survival Not Improved With Dose-Dense Chemotherapy for Small-Cell Lung Cancer

Wed, 04 May 2005 17:25:38 PST

( from http://www.rxpgnews.com ) A randomized trial has found that a dose-dense regimen of chemotherapy with blood progenitor cell support did not improve survival compared with standard-dose chemotherapy in patients with small-cell lung cancer (SCLC). However, patients who received the dose-dense regimen had fewer infections and fewer days of treatment than patients who received standard chemotherapy.

Long-term survival in patients with SCLC is poor. Studies that have tested different dose intensities of various chemotherapy regimens for SCLC have yielded conflicting results. Paul Lorigan, M.D., of Christie Hospital Manchester in England, and colleagues conducted a phase III randomized trial to determine whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with blood-progenitor-cell support improved survival compared with standard ICE chemotherapy in patients with SCLC who had a relatively good prognosis. A total of 318 patients were randomly assigned to receive ICE chemotherapy every 4 weeks (standard arm) or every 2 weeks (dose-dense arm).

Overall survival and 2-year survival were similar in the two arms. The treatment duration was shorter in the dose-dense arm than in the standard arm, but this difference was not statistically significant.

Age not a Limiting Factor in Lung Cancer Therapy

Tue, 26 Apr 2005 02:01:38 PST

( from http://www.rxpgnews.com ) Elderly lung cancer patients tolerate combined chemotherapy and radiotherapy with no higher risk of death than younger patients, according to a new study appearing in the June 1, 2005 issue of CANCER (http://www.interscience.wiley.com/cancer-newsroom), a peer-reviewed journal of the American Cancer Society

Lung cancer remains the leading cause of cancer deaths in the U.S., with half of those diagnosed at age 70 years or older. About 20 percent of patients with lung cancer will have small cell lung cancer (SCLC). In the past, SCLC progressed rapidly despite initial chemotherapy sensitivity and few patients survive three years.

New treatment modalities have provided encouraging results. Studies have found chemotherapy combined with radiotherapy improves survival over chemotherapy alone. Since that finding, researchers have developed new protocols for combined modality treatment to improve survival. Investigators led by Steven E. Schild, M.D. of the Mayo Clinic and the North Central Cancer Treatment Group conducted a clinical trial using two different approaches to combined therapies. Using data from this trial, they sought to evaluate the role of age in therapy tolerance, disease control, and survival following combined modality therapy.

They found that two- and five-year survival rates and disease progression rates were not significantly different for patients younger than 70 compared to those 70 years of age and older. At five years, 22 percent of patients younger than 70 were living compared to 17 percent of elderly patients. This difference is not statistically significant. While overall toxicity was similar between the two age groups, specific moderate and severe toxicities occurred more frequently in the elderly. Severe pneumonitis requiring ventilation or continuous oxygen was significantly more common in the elderly, occurring in 6 percent of elderly patients compared to no patients in the younger age group.

Based on their findings, the authors conclude: "fit elderly patients with locally advanced limited stage small cell lung cancer should be encouraged to receive combined modality therapy, preferably on clinical trials."

Early detection of Lung Cancer

Wed, 20 Apr 2005 20:18:38 PST

( from http://www.rxpgnews.com ) This study was aimed at the detection of lung cancer in its early stages amongst high-risk persons by means of Computerised Axial Tomography (CAT).

Currently, 85% of cases are diagnosed at a late stage, which considerably reduces the rate of cure.

Lung cancer is the most common carcinoma in western countries and the one that causes most deaths; more than those caused by breast cancer, cancer of the colon and prostate cancer put together.

Tobacco is the main cause of this illness, with the risk of it arising persisting even twenty years after giving up smoking. In general this pathology is diagnosed on its symptoms appearing, indicating that it is at an advanced stage and with poor prognosis. In fact, using traditional techniques, only 15% of cases are detected at an early stage; this is why it is essential to find tools for early detection which will guarantee the curing of the illness.

The research by the Lung Service at the Navarre University Hospital used thoracic CAT to periodically analyse persons at high risk of developing lung cancer, i.e. over-forties who have smoked at least one packet a day over ten years. The study is part of the ELCAP (Early Lung Cancer Action Program), international project in which centres from the United States, Europe, Japan, China and Israel participated.

Results

The research proved the efficacy of this imaging technique for the early-stage detection of lung cancer. The published results correspond to the first 1000 persons who took part in the project at the University Hospital. Concretely, cancer was detected in 14 individuals, thirteen at stage 1, the earliest and most curable stage. This work confirmed the conclusions obtained by ELCAP from more than 30,000 persons.

Despite the direct link between tobacco and lung cancer, only 15% of smokers develop the disease. Thus, it is fundamental to find any risk factors that predispose having this pathology. This study discovered that there was a greater risk amongst asymptomatic smokers than amongst those who were diagnosed with obstructive pulmonary disease with spirometry. In any case, it is essential to continue with these lines of research aimed at identifying the population at high risk with precision. Specifically, a priority line of investigation at the University Hospital and the CIMA Centre at Navarre University involves the study of biomolecular techniques and their combination with radiological tests that help in the early detection of lung cancer.

Once the first results are published, the project will continue to review, by means of CAT, those patients who have not developed the illness. What is wanted is a better definition of the use of this technique in order to judge its efficacy in the detection of new cancers amongst this population at risk. Moreover, the effect of this monitoring on the weaning of participants off the tobacco habit will be analysed.

Clinical Trial of Gefitinib for Advanced Lung Cancer Closes Early

Wed, 20 Apr 2005 19:22:38 PST

( from http://www.rxpgnews.com ) Researchers have closed a randomized clinical trial comparing gefitinib (Iressa) vs. placebo following chemotherapy and radiation for patients with non-small cell lung cancer (NSCLC) that had spread only to nearby tissues or lymph nodes. Review of interim data indicated that gefitinib would not improve survival.

The clinical trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health in Bethesda, Md., and was conducted by a network of researchers led by the Southwest Oncology Group (SWOG), Ann Arbor, Mich. AstraZeneca Pharmaceuticals LP, Wilmington, Del., which manufactures gefitinib, provided the agent for the trial under the Clinical Trials Agreement with NCI for the development of gefitinib. Iressa is a drug that inhibits an enzyme (tyrosine kinase) present in lung cancer cells, as well as other cancers and normal tissues, that appears to be important to the growth of cancer cells.

Based on a review of the limited data available from the Phase III clinical trial, the Data Monitoring Committee overseeing the trial (known as S0023*) recommended the closure, as the trial would not meet its primary endpoint of improved survival. Detailed results from the study will be presented at the American Society of Clinical Oncology Annual Meeting (ASCO) on May 14, 2005.

The study was designed to assess whether maintenance therapy with gefitinib -- gefitinib given to help keep cancer in control -- would improve overall survival and progression-free survival as compared to placebo in patients with stable or responding disease. These patients had inoperable stage III NSCLC and already had completed the combined chemotherapy regimen of cisplatin and etoposide with radiation, followed by docetaxel. A total of 672 patients in this study were to be randomized to one of two treatment arms following chemotherapy and radiation: one arm would receive gefitinib daily and the other arm would receive a placebo daily. As of March 10, 2005, 611 patients were entered and 276 were randomized to one of the two arms.

"The interim analysis indicates that even with accrual of more patients or with longer follow-up, the gefitinib arm would not improve survival," said Laurence Baker, D.O., chairman of SWOG and professor of internal medicine and pharmacology at the University of Michigan in Ann Arbor. This analysis did confirm, however, the favorable survival seen with the chemotherapy and radiation regimen previously reported by SWOG**, and thus patients currently entered in the trial are being advised to complete this part of their treatment.

"Based on the analysis, the use of gefitinib following chemotherapy and radiation should not be prescribed for this group of patients," said Scott Saxman, M.D., who oversees lung cancer clinical trials for NCI.

An estimated 172,570 people will be diagnosed with lung cancer in the United States in 2005. Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death in both men and women in this country. An estimated 163,510 deaths from lung cancer will occur in 2005 in the United States, accounting for about 29 percent of all cancer-related deaths in the nation.

Abnormal lung cancer screening results may help smokers quit

Mon, 11 Apr 2005 12:40:38 PST

( from http://www.rxpgnews.com ) According to a new study, smokers who receive multiple abnormal results using computed tomography (CT) to screen for lung cancer are more likely to quit, suggesting an opportunity for doctors to motivate smokers to quit smoking. The study appears in the May 15, 2005 issue of CANCER, a peer-reviewed journal of the American Cancer Society, and finds smokers who receive one or more abnormal results on the screening test are increasingly likely to quit and remain abstinent from smoking over three years.

Because up to 70 percent of smokers undergoing screening say they want to quit, many researchers have been interested in using cancer screening results as an opportunity to motivate smokers to quit. Previous studies have found smokers recently diagnosed with medical conditions are more interested in, and successful at, quitting.

Studies of low-dose, fast, spiral chest CT have supported its use as a potential "teachable moment" to motivate a smoker to quit. A previous study published in CANCER indicated a single, annual CT lung cancer screening did not increase smoking cessation rates. Therefore, perhaps, multiple abnormal findings may provide a psychological push for a smoker to quit.

Seeking to test that hypothesis, investigators led by James R. Jett, M.D. and Stephen J. Swensen, M.D. at the Mayo Clinic in Rochester, MN followed 926 baseline smokers and 594 former smokers who received three consecutive annual spiral CT scan screenings for lung cancer.

According to Matthew M. Clark, Ph.D., a psychologist working with the investigative team, they found that the more abnormal screenings a smoker received, the more likely they were to quit and remain smoke free at the end of three years. After the third annual follow-up visit, 42 percent of baseline smokers who had three abnormal scans were abstinent from smoking, compared to 28 percent who had two abnormal scans and 24 percent and 20 percent who had one or no abnormal scans, respectively. Factors that contributed to smoking abstinence among baseline smokers were older age, worse baseline pulmonary function, and previous year abnormal CT findings.

Explaining the results, the authors conclude, "multiple lung CT scans may enhance primary and secondary prevention efforts by potentially providing increased interaction with health care providers, increased cognitions about one's own cancer risk, and reinforcement for smoking abstinence with lung CT scan screening."

Aerosolized Cyclosporine Shows Significant Results in Chronic Rejection of Allogenic Lung Transplants

Thu, 24 Mar 2005 09:21:38 PST

( from http://www.rxpgnews.com ) The Pulmonary-Allergy Drugs Advisory Committee will review Chirons aerosolized cyclosporine Pulminiq for lung transplantation June 6.

The committee discussion likely will focus on additional analyses of pivotal data.

Chiron confirmed that FDA extended aerosolized cyclosporines priority review deadline of April 15 by 90 days following the firms submission of additional analyses earlier this year.

The company had been expecting the 90-day extension following FDAs request for further analysis of the NDAs pivotal trial.

The aerosolized cyclosporine NDA (50-799) includes a single pivotal trial that showed significant results in chronic rejection of allogenic lung transplants, but not in acute rejection.

Chiron is seeking approval for use of aerosolized cyclosporine in combination with standard immunosuppressive therapy to increase survival and prevent chronic rejection in patients receiving allogenic lung transplants.

This would be the first immunosuppresant approved for the indication, Chiron said.

Bevacizumab plus Chemotherapy can Prolong Lung Cancer Survival

Fri, 18 Mar 2005 23:40:38 PST

( from http://www.rxpgnews.com ) Preliminary results from a large, randomized clinical trial for patients with previously untreated advanced non-squamous, non-small cell lung cancer show that those patients who received bevacizumab (AvastinTM) in combination with standard chemotherapy lived longer than patients who received the same chemotherapy without bevacizumab.

The clinical trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a network of researchers led by the Eastern Cooperative Oncology Group. Genentech, Inc., South San Francisco, Calif., which manufactures bevacizumab, provided bevacizumab for the trial under the Cooperative Research and Development Agreement (CRADA) with NCI for the clinical development of bevacizumab.

The Data Monitoring Committee overseeing the trial (known as E4599)* recommended that the results of a recent interim analysis be made public because the study had met its primary endpoint of improving overall survival. Researchers found that patients in the study who received bevacizumab in combination with standard chemotherapy (a treatment regimen of paclitaxel and carboplatin) had a median overall survival of 12.5 months compared to patients treated with the standard chemotherapy alone, who had a median survival of 10.2 months. This difference is statistically significant. Detailed results from this trial will be presented at the American Society of Clinical Oncology Annual Meeting (ASCO) to be held in Orlando, Fla., on May 13-17, 2005.

"The exciting results of this randomized study reveal, for the first time, an improvement in survival with the addition of a targeted agent to standard chemotherapy in this patient population," said Study Chair Alan B. Sandler, M.D., of the Vanderbilt University Medical Center in Nashville, Tenn.

"This study demonstrates that mechanistic-based interventions such as angiogenesis inhibitors are making important contributions in improving cancer outcomes," said NCI Director Andrew C. von Eschenbach, M.D. "In combination with standard therapies, they can be used for a variety of cancers, leading to increased patient survival."

A total of 878 patients with advanced non-squamous, non-small cell lung cancer (NSCLC) who had not previously received systemic chemotherapy were enrolled in this study between July 2001 and April 2004. Patients were randomized to one of the two treatment arms. One patient group received standard treatment -- six cycles of paclitaxel and carboplatin. The second group received the same six-cycle chemotherapy regimen with the addition of bevacizumab, followed by bevacizumab alone until disease progression.

Patients with squamous cell carcinoma of the lung were not included in the study because previous clinical experience suggested that patients with this particular type of NSCLC had a higher risk of serious bleeding from the lung after bevacizumab therapy. Patients with a prior history of frank hemoptysis (coughing up blood) were also not enrolled on the trial.

The most significant adverse event observed in this study was life-threatening or fatal bleeding, primarily from the lungs. This occurred infrequently, but was more common in the patient group that received bevacizumab in combination with chemotherapy than in the patient group that received only chemotherapy. A full description of side effects observed in this trial will be presented at the ASCO Annual Meeting in May, as well.

Bevacizumab, a humanized monoclonal antibody**, is designed to bind to and inhibit vascular endothelial growth factor (VEGF). VEGF is a protein that plays a critical role in tumor angiogenesis, the formation of new blood vessels to the tumor.

"This trial represents another step in a series of recent important advances in treatment for patients with advanced lung cancer," said James H. Doroshow, M.D., director of NCI's Division of Cancer Treatment and Diagnosis and leader of NCI's Clinical Trials Working Group. "Important progress continues to be made by targeting molecular pathways critical to the growth and survival of cancer cells. It is through better understanding of these molecular processes that significant advances will be made in the treatment of this disease."

An estimated 172,570 people will be diagnosed with lung cancer in the United States in 2005. Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death in both men and women in this country. An estimated 163,510 deaths from lung cancer will occur in 2005 in the United States, accounting for about 29 percent of all cancer-related deaths in the nation.

Adding Bevacizumab in First-Line Chemotherapy Regimen Improves Overall Survival in Non-Squamous, Non-Small Cell Lung Cancer

Tue, 15 Mar 2005 11:30:38 PST

( from http://www.rxpgnews.com ) Genentech, Inc. and Roche today announced that an interim analysis of a Phase III study of Avastin(TM)(bevacizumab) plus paclitaxel and carboplatin chemotherapies in first-line non-squamous, non-small cell lung cancer (NSCLC) met its primary efficacy endpoint of improving overall survival, or a reduction in the risk of death, compared to chemotherapy alone.

The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, under a Cooperative Research and Development Agreement between NCI and Genentech, Inc., and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG).

According to ECOG, data from this study will be submitted to the annual meeting of the American Society of Clinical Oncology (ASCO), May 13 - 17, 2005.

"These results represent the first study combining a targeted biologic therapy with chemotherapy to show an overall survival improvement in the first-line non-small cell lung cancer setting, and the first time that any treatment has improved upon the standard, two-drug chemotherapy regimen in this disease," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer.

"We would like to thank our collaborators at NCI and ECOG for their work on this study, as well as the many patients and their families who made the decision to participate in this study. We plan to share these data with the FDA to discuss the possibility of filing a supplemental Biologics License Application for bevacizumab plus chemotherapy in first-line non-small cell lung cancer."

This is the first Phase III study to evaluate the therapeutic antibody bevacizumab in combination with chemotherapy in NSCLC. This was a randomized, controlled, multicenter trial that enrolled 878 patients with previously- untreated advanced NSCLC. The patients enrolled in this trial were randomized to receive treatment with paclitaxel and carboplatin chemotherapies with or without bevacizumab.

In previous clinical experience with bevacizumab in combination with paclitaxel and carboplatin in NSCLC, life-threatening or fatal pulmonary bleeding was identified as a severe adverse event apparently unique to this disease.

Certain characteristics, including any significant pulmonary bleeding prior to receiving treatment with bevacizumab or the presence of a specific type of NSCLC called squamous cell carcinoma appeared to predispose patients to experiencing this adverse event.

Patients with these characteristics were excluded from this Phase III study and the rate of life- threatening or fatal pulmonary bleeding was substantially reduced from prior clinical studies. However, some patients did experience fatal pulmonary bleeding in this trial and this event was more common in the patient group that received bevacizumab in combination with chemotherapy than in the patient group that received chemotherapy only.

Other adverse events observed in this study were similar to those identified in previous Phase II and Phase III studies of bevacizumab. More detailed information about adverse events in this study will be presented at the ASCO meeting in May.

Bevacizumab is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumor angiogenesis and maintenance of existing tumor vessels. By binding to VEGF, bevacizumab is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis.

The FDA approved bevacizumab on February 26, 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. Approval was based on data from two trials. The pivotal trial was a large, placebo-controlled, randomized study of 925 patients that demonstrated a prolongation in the median survival of patients treated with bevacizumab plus the IFL (5-FU/leucovorin/CPT-11) chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months).

In addition, this study demonstrated an improvement in progression-free survival (PFS) of more than four months (10.6 months in the bevacizumab/IFL arm compared to 6.4 months in the IFL-alone arm).

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with bevacizumab evaluating its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, non-small cell lung and ovarian cancers. Bevacizumab is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumor cancers and hematologic malignancies.

Bevacizumab has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with bevacizumab were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure.

The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the bevacizumab arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the bevacizumab arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.

The link between angiogenesis and cancer growth has been discussed by many researchers for decades. It wasn't until 1989 that a key growth factor influencing the process, VEGF, was discovered by Napoleone Ferrara, M.D., a staff scientist at Genentech. Dr. Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. This research was published in the journal Science in 1989. Dr. Ferrara then created a mouse antibody to this protein.

In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumor growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumor growth. Clinical studies with a humanized version of the antibody, bevacizumab, began in 1997.

According to the World Health Organization, there are more than 1.2 million cases worldwide of lung and bronchial cancer each year, causing approximately 1.1 million deaths annually. An estimated 173,000 people were diagnosed with lung cancer in the United States in 2004. According to the National Cancer Institute, lung cancer is the single largest cause of cancer deaths in the United States and is responsible for nearly 30 percent of cancer deaths in this country. NSCLC is the most common form of the disease and accounts for almost 80 percent of all lung cancers.

Women may be more susceptible to lung cancer than men due to estrogen

Wed, 16 Feb 2005 19:43:38 PST

( from http://www.rxpgnews.com ) New and effective treatments for lung cancer may rest on their ability to hinder the action of estrogen in lung cancer cells, according to two studies published in the current issue of Cancer Research. The University of Pittsburgh studies build on current knowledge about the relationship between estrogen and lung cancer growth and suggest that blocking estrogen may be vitally important to improving survival from the disease.

Since 1930, a 600 percent increase in death rates from lung cancer has been reported in women in the United States, leading some experts to suggest that women may be more susceptible to lung cancer than men. The current research contends that this could be due to the effects of estrogen on the lungs.

"Our studies continue to show that lung cancer cells grow in response to estrogen and that stopping or slowing the spread of the disease may be dependent on blocking the action of estrogen," said Jill Siegfried, Ph.D., professor, department of pharmacology and co-leader, Lung and Thoracic Malignancies Program, University of Pittsburgh Cancer Institute. "In fact, in previous studies, we have observed that lung tumor cells contain estrogen receptors at levels comparable to breast cancer cells." A receptor is a structure on the surface of a cell that selectively receives and binds substances.

In the first study, Laura Stabile, Ph.D., instructor in the department of pharmacology at the University of Pittsburgh, and colleagues examined methods to block the action of estrogen in human lung tumors grafted in mice. They compared the effect of blocking the estrogen receptor (ER) pathway alone to blocking it in combination with another receptor pathway the epidermal growth factor receptor (EGFR). The investigators combined an agent approved for inhibiting the EGFR pathway, gefitinib (Iressa®), with an anti-estrogen agent, fulvestrant (Faslodex®) a treatment commonly used to manage breast cancer in women with ER positive tumors, but not yet approved for clinical lung cancer treatment. They found that the combined treatment resulted in a tumor volume decrease of 59 percent, compared to a 49 percent decrease for gefitinib treatment alone and a 32 percent decrease for fulvestrant treatment alone. They also found that lung tumors in the combined treatment group were comprised mainly of dead and dying cells, while the number of these cells in the single treatment groups was significantly lower. The study suggests that an interaction between treatments that target both ER and EGFR may enhance the anti-tumor effects of therapy over the use of each agent alone. A pilot clinical trial is already underway testing the combination therapy in women with advanced lung cancer.

"Evidence from our study confirms what has been described for breast cancer that blocking the estrogen receptor and the epidermal growth factor receptor pathways together is more effective," said Dr. Stabile.

In the second study, Pamela Hershberger, Ph.D., assistant professor in the department of pharmacology at the University of Pittsburgh, examined the effect of estrogen on the expression of genes in lung cancer cells. Using gene arrays, Dr. Hershberger and colleagues reported that some of the same growth genes induced by estrogen in breast cancer also are regulated by estrogen in lung cancer. In addition, the same estrogen inhibitor, fulvestrant, that was active against lung cancer in Dr. Stabile's study also blocked the ability of estrogen to regulate lung cancer cell gene expression. Dr. Hershberger's study further showed that other proteins needed for ER to act in breast cancer are found in lung cancer cells.

"Both of these studies clearly suggest that lung cancer cells respond to estrogen and that improving overall patient survival may be contingent upon identifying therapies that target specific pathways and put a halt to estrogen signaling," said Dr. Siegfried.