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." 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.
The study's lead authors are J. Guillermo Paez, Ph.D., and Pasi Janne, M.D., Ph.D., of Dana-Farber and Brigham and Women's Hospital, and Jeffrey Lee, of Dana-Farber and Harvard Medical School (HMS).
"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."
In the study, 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, study co-authors 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 remarks. "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."
The study's 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.
Funding for the study came from 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.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Editor's Note: Copies of the paper are available through the AAAS Office of Public Programs, 202-326-6440, or scipak@aaas.org. More information on the Kinase Project is available online, http://www.dana-farber.org/abo/news/publications/pop/fall-winter-2003/kinase.asp.
Contact: Bill Schaller or Rob Levy (617) 632-5357
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