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Study identifies which patients can benefit from Iressa, targeted lung cancer drugPSA Rising April 29, 2004 /BOSTON/  In a study that stands to benefit thousands of patients with non-small cell lung cancer around the world, researchers at Dana-Farber Cancer Institute and in Japan have found that patients whose lung cancers harbor a malfunctioning version of a protein called EGFR respond dramatically to the drug gefitinib (IressaTM). The findings are the first fruit of an approach that seeks a systematic route to the development of new cancer therapies. By scanning the DNA of cancer cells, Dana Farber scientists and colleagues at the Massachusetts Institute of Technology's Broad Institute are hunting for mutated genes that instruct cells to produce abnormal versions of growth proteins called tyrosine kinases. The hope is that drugs known to block such proteins can stymie cancer growth while leaving normal cells intact. The study will be published this week in the online version of the journal Science (www.sciencemag.org). Related research from Massachusetts General Hospital Cancer Center, a member of the Dana-Farber/Harvard Cancer Center, will be concurrently released online by the New England Journal of Medicine on April 29. "Imatinib (GleevecTM) [which has halted or shrunk tumors in patients with a form of leukemia and digestive-system tumor] is probably the best-known example of a drug that works by targeting a specific, mutated tyrosine kinase," says William Sellers, M.D., who is co-senior author of the study with his Dana-Farber colleagues Bruce Johnson, M.D., and Matthew Meyerson, M.D., Ph.D. "So far, though, this approach has been most notable in cancers that are relatively rare. Our study shows that it can be effective for a common form of cancer as well," Sellers said. Non-small cell lung cancer (NSCLC) accounts for about 85 percent of all cases of lung cancer, the number one cancer killer of both men and women in the United States. "Until now, there has not been a great deal that medicine could do for most patients with non-small cell lung cancer," says Meyerson, who is also on the faculty of the Broad Institute and HMS. "This study is the first indication that a therapy targeted for a specific group of patients can have an impact on this disease. It demonstrates how the growing understanding of human biology and the Human Genome Project are converging to produce an immediate effect on cancer care." Dana-Farber and Broad investigators led by Meyerson and Sellers scanned non-small cell lung tumors from 58 Japanese and 61 American patients for gene mutations. While just one of the American patients had a mutation in the gene for EGFR (which stands for "epidermal growth factor receptor"), 15 of the Japanese patients did. The investigators knew from previous research that Iressa, an EGFR kinase blocker that has had only sporadic success against NSCLC, shrinks such tumors more frequently in Japanese patients than in Americans. Meanwhile, Johnson and Janne found that tumor tissue from a woman with cancer that had spread to the lining around her lungs-- a condition called adenocarcinoma  was very responsive to gefitinib when tested in a laboratory dish. When the adenocarcinoma's DNA was analyzed, it was found to have the same EGFR gene mutation that Meyerson and Sellers' group had found. "We were struck that certain groups of NSCLC patients appear to be more likely to have EGFR mutations than others," Johnson said. "Mutations were more frequent in women, in Japanese patients, and in patients with adenocarcinoma. These are the exact same groups that are most likely to experience tumor shrinkage when treated with gefitinib. Because Iressa is an EGFR inhibitor, we reasoned that patients with EGFR mutations might be especially responsive to treatment with Iressa." To test that idea, investigators analyzed tumor samples from five patients who had been successfully treated with Iressa and four patients whose tumors did not respond. All of the responders were found to have EGFR mutations, while none of the four whose lung cancers did not respond had mutations. "Our results suggest that screening patients for EGFR mutations can help predict whether they will be responsive to treatment with Iressa," comments Johnson, who is also a faculty member at Brigham and Women's and HMS. "They also point to the fact that certain ethnic populations may benefit from Iressa therapy to a greater degree than others." The Dana-Farber team's next step will be to conduct clinical trials to determine if combining Iressa with other targeted treatments can benefit patients not helped by Iressa alone. They hope to undertake these studies with colleagues at Massachusetts General Hospital who are also engaged in kinase research. The Science study stems from a program at Dana-Farber and the Broad Institute that has come to be known as the Kinase Project. The project, which grew out of a conversation between Sellers and Meyerson while traveling to a science conference, seeks to identify abnormal tyrosine kinases  enzymes that spark or halt growth  in cancer cells and test agents known to act against them. "The focus on kinases grew out of the idea that they may offer a way to have an immediate impact on cancer," remarks Sellers, who is also on the faculty at the Broad Institute and HMS. "This study demonstrates that rational drug design  developing drugs based on an understanding of basic biological processes  offers real hope in changing the course of cancer care and treatment." Other authors include Sean Tracy, Heidi Greulich, Ph.D., Paula Herman, Titus Boggon, Ph.D., Katsuhiko Naoki, M.D., Ph.D., and Michael Eck, M.D., Ph.D., of Dana-Farber; Stacey Gabriel, Ph.D., of the Broad Institute; Frederic Kaye, M.D., of the National Cancer Institute; Neal Lindeman, M.D., of Brigham and Women's; and Hidefumi Sasaki, M.D., and Yoshitaka Fujii, M.D., of Nagoya City University Medical School in Japan. The project was paid for by the Claudia Adams Barr program at Dana-Farber, the Novartis Research Foundation, and the Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Program in Research Excellence. Copies of the paper are available through the AAAS Office of Public Programs, 202-326-6440, or [email protected]. More information on the Kinase Project is available online from Dana Farber. reported by J. Strax, last updated April 2004.
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