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The AACR Increases Focus On Clinical Trials

April 3, 2011

The American Association for Cancer Research Annual Meeting continues to be a showcase for the most cutting edge science in cancer, and this year’s meeting, held here April 2-6, will include an increased focus on clinical trials that will impact patient care.

Daniel D. Von Hoff, M.D., physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen), professor of medicine at the Mayo Clinic, and chief scientific officer at Scottsdale Healthcare and U.S. Oncology Research, will host a press conference on Saturday, April 2 at 10:00 a.m. ET in room W313 of the Orange County Convention Center.

“Scientists in the drug development arena are rethinking how trials are conducted in the wake of so much new knowledge about biomarkers and genetics,” he said. “These results will show how it is playing out in both treatment and prevention of lung cancer, breast cancer and other hard to treat malignancies.”

The following research will be presented during this press conference:

    * New Inhibitor Prevented Lesions, Reduced Tumor Size in Basal Cell Cancer
    * BATTLE Researchers Identify New Biomarkers for EGFR Inhibition
    * Combining MEK and PI3K Inhibitors Appears Encouraging in a Safety Study with Early Signs of Anti-tumor Activity
    * Target for Lung Cancer Chemoprevention Identified
    * DNA of 50 Breast Cancer Patients Decoded

Reporters who cannot attend in person can participate by using the following information:

    * U.S. & Canada: (888) 647-7462
    * International: (201) 604-0169
    * Access Code: 244078

New Inhibitor Prevented Lesions, Reduced Tumor Size in Basal Cell Cancer

A new hedgehog pathway inhibitor demonstrated efficacy in preventing and treating basal cell cancer among patients with basal cell nevus syndrome, a rare inheritable disease, according to Phase II data presented at the AACR 102nd Annual Meeting 2011, held April 2-6.

In 1996, Ervin Epstein Jr., M.D., senior scientist at Children’s Hospital of Oakland Research Institute, and colleagues identified the site of the mutation that causes basal cell nevus syndrome: the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway. This pathway provides information for the proper development of an embryo; when the pathway malfunctions in adulthood it can produce basal cell carcinomas, the most common human cancer.

Using this information, researchers developed GDC-0449, which Epstein said “is the first drug in man that is an anti-hedgehog signaling pathway drug.”

“These data are a triumph for the idea that if you really understand the fundamental flaw in cancer, you can attack it in a much more specific way and avoid side effects of the more traditional chemotherapy,” he said.

Phase I data have shown that GDC-0449 reduced locally advanced/metastatic basal cell carcinomas. For this randomized, double-blind, placebo-controlled trial, the researchers enrolled 41 patients who had basal cell nevus syndrome. They randomly assigned patients to receive 150 mg GDC-0449 or placebo.

During the interim analysis, the data safety monitoring board stopped the placebo arm of the trial because of statistically significant differences between patients receiving GDC-0449 and those receiving placebo. Those patients treated with GDC-0449 developed 0.07 new basal cell carcinomas per month compared with 1.74 new basal cell carcinomas per month among those who recieved placebo. The size of existing basal cell carcinomas decreased significantly in the GDC-0449 group but was essentially unchanged in the placebo group.

None of the patients who received GDC-0449 required surgical removal of any basal cell carcinoma (BCC) during the course of the study “” a significant finding for these patients who can develop many lesions that require surgical removal multiple times a month.

“These tumors disappear completely; all of them have vanished after somewhere between six and 12 months,” Epstein said. “There’s an immediate diminution that you can recognize after one or at most two months of treatment, and so far we have not seen any BCC that developed resistance to the drug.”

Common side effects included loss of taste, muscle cramps and weight loss. Two patients experienced grade 3 to 4 adverse events including muscle cramps as well as a suicide attempt in one patient who made two such attempts prior to beginning study medication. Twenty percent of patients discontinued GDC-0449 because of side effects.

Although the researchers hope to use GDC-0449 and other hedgehog inhibitors vs. single sporadic BCC tumors eventually, Epstein explained that it may be impractical for a patient with a single tumor to endure the side effects of these inhibitors when they have small single lesions that can be removed surgically.

“In the regimen given, it’s unlikely that GDC-0449 would be adopted for many patients with sporadic basal cell carcinomas,” Epstein said. “But clearly our findings indicate that basal cell carcinomas are highly susceptible to this drug, and with different delivery and different dosing, perhaps some of these lesions might be eventually treated with such chemical entities as opposed to surgery.”

BATTLE Researchers Identify New Biomarkers for EGFR Inhibition

Scientists are continuing their work on the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination trial “” known more commonly as the BATTLE trial “” and presented updated results at the AACR 102nd Annual Meeting 2011, held here April 2-6.

John Heymach, M.D., Ph.D., associate professor of thoracic, head and neck medical oncology at The University of Texas MD Anderson Cancer Center, said this update details the “discovery phase” of the ongoing program.

“Last year, we presented results on pre-specified markers to determine how effective they would be at predicting response to EGFR inhibition. This year we worked in the other direction to try to discover and test novel gene markers that hadn’t been pre-specified,” said Heymach.

Researchers performed gene expression profiling and core needle biopsies on 101 patients in the BATTLE trial. They found that the presence of an EMT (epithelial-to-mesenchymal signature) and the presence of a novel five gene signature including LCN2 were predictive of response to erlotinib, including patients with wild-type EGFR, as measured by disease control rate and progression-free survival.

Heymach said thus far new markers were identified retrospectively in the BATTLE protocol. The upcoming BATTLE 2 protocol will test the predictive value of these gene signatures prospectively.

“The hope is that we’ll be able to predict who will respond to EGFR inhibition with erlotinib, particularly among patients who do not have an EGFR mutation. We currently don’t have any predictive markers for this group of patients. We also think a similar approach can be applied to other drugs,” he said.

The first results of BATTLE, which were presented at the AACR 101st Annual Meeting 2010, are published in Cancer Discovery, the newest journal of the American Association for Cancer Research, debuting at this year’s Annual Meeting on Sunday, April 3.

Combining MEK and PI3K Inhibitors Appears Encouraging in a Safety Study with Early Signs of Anti-tumor Activity

The combination of two compounds that inhibit two of the most frequently mutated cancer pathways is showing promise in an ongoing Phase I trial, according to data presented at the AACR 102nd Annual Meeting 2011, held here April 2-6.

The research, presented by Johanna Bendell, M.D., tests a combination of GDC-0973, which inhibits MEK1/2 and GDC-0941, which inhibits PI3K. Bendell, director of Gastrointestinal Oncology Research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, said the RAS/RAF/MEK and PI3K pathways are altered in most tumors.

“Combining agents that block multiple pathways in tumor cells is likely the future of targeted therapy in cancer medicine. Blocking two pathways that interact with each other has the potential to have more anti-cancer activity than blocking either pathway alone,” says Bendell.

The researchers enrolled 27 patients who received the combination of different doses of GDC-0973 and GDC-0941 on a daily 21 day on/7 day off schedule. The most common side effects seen were diarrhea, fatigue, rash, nausea, vomiting, decreased appetite and taste changes. Most of these side effects were mild.

Several patients have demonstrated decreases in tumor size, including two patients with melanoma, one with prostate cancer, two with non-small cell lung cancer. One patient with lung cancer and two patients with melanoma had stable disease over six months. The study is ongoing.

“We are very encouraged by this early data. We are able to give these agents together safely and we are seeing early signs of anti-cancer activity,” said Bendell.

Target for Lung Cancer Chemoprevention Identified

Scientists have identified a biomarker for measuring the success of lung cancer chemoprevention, an emerging frontier in the fight against this disease that has long been stymied by a lack of measureable outcomes. These study results were presented at the AACR 102nd Annual Meeting 2011, held April 2-6.

Paul Bunn, M.D., executive director of the International Association for the Study of Lung Cancer and the James Dudley endowed professor of lung cancer research at the University of Colorado Cancer Center at the University of Colorado School of Medicine, said measurements of endobronchial dysplasia, abnormal cell development that can lead to lung cancer, could predict how well a chemoprevention agent is working.

Bunn presented updated results of a study that tested the effect of oral iloprost on the improvement on endobronchial dysplasia in 152 former smokers. As smoking cessation messages take hold and quit rates increase, former smokers are still at greater risk for lung cancer than the general population.

“We told people to quit smoking and they did, but half of our lung cancer cases in the United States are coming from people who are former smokers,” he said. “We need to work on ways to repair their lungs through chemoprevention.”

Bunn analyzed the effect of iloprost among those who had endobronchial dysplasia at enrollment, and found a significant difference in prevalence of endobronchial dysplasia. Moreover, when they analyzed the effect of iloprost on Ki-67, a measure of cell proliferation, the difference was not significant.

This is an important advancement for the chemoprevention field, Bunn said, because it shows that they can test agents, like iloprost, and measure the effect on endobronchial dysplasia as an outcome. Chemoprevention is a goal for cancer researchers, and many of them liken the idea to heart disease prevention with statins, a major public health advance of the past 50 years.

“The challenge is there has been no real equivalent to cholesterol with cancer. This study shows that endobronchial dysplasia could play that role,” he said.

DNA of 50 Breast Cancer Patients Decoded

In one of the largest cancer genomics investigations reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients’ healthy cells. This comparison allowed researchers to find mutations that only occurred in the cancer cells.

Researchers uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The research was presented at the AACR 102nd Annual Meeting 2011, held April 2-6.

In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, said Matthew Ellis, M.D., Ph.D., professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project.

“Cancer genomes are extraordinarily complicated,” said Ellis. “This explains our difficulty in predicting outcomes and finding new treatments.”

Washington University oncologists and pathologists at the Siteman Cancer Center collaborated with the university’s Genome Institute to sequence more than 10 trillion chemical bases of DNA “” repeating the sequencing of each patient’s tumor and healthy DNA about 30 times to ensure accurate data.

The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients had estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumors grow.

To slow tumor growth and make the tumors easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work; only 26 of the 50 tumor samples responded. Comparing the responders and those who were resistant might help explain why some ER-positive breast cancer patients do well with estrogen-lowering drugs and others poorly.

Confirming previous work, the researchers found that two mutations were relatively common in many of the patients’ cancers. PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen and TP53 is present in about 20 percent. Ellis and colleagues found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of ER-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.

“To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock,” he said.

In addition, they found 21 genes that were also significantly mutated, but at much lower rates “” never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stressed their importance.

“Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women,” he said.

Ellis pointed out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them. But such treatment is only possible when the cancer’s genetics are known in advance. Ideally, the goal is to design treatments by sequencing the tumor genome when the cancer is first diagnosed, according to Ellis.

“We get good therapeutic ideas from the genomic information,” he said. “The near term goal is to use information on whole genome sequencing to guide a personalized approach to the patient’s treatment.”

While many mutations are rare or even unique to one patient, Ellis said quite a few can be classified on the basis of common biological effects and, therefore, could be considered together for a particular therapeutic approach.

Ellis looks to future work to help make sense of breast cancer’s complexity. But these highly detailed genome maps are an important first step.

“At least we’re reaching the limits of the complexity of the problem,” he said. “It’s not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome.”

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