Oncology: Mutated Target Gives Potency to Lung Cancer Medication Education: Harvard Introduces Joint MD-MBA Pathology: Suppressor Cell Subset Crucial Against Autoimmunity Health Policy Summers Urges Analytic Approach to Advancing Care Digestive Protein Directs Fats to Immune System Small, Frequent Doses of Caffeine Best for Staying Awake Tobacco Use in India Hits the Poor Hardest   Proceedings of the HMS Faculty Council Three Endowed Chairs Named in Sleep Medicine Alumni Week Preview HSDM Scholars Program Advances Dental Education Research Armenise Foundation Awards Junior Faculty Grants First Annual "Doctors' Night at Symphony Hall"   Students Mentor Youths at Community Health Center   On Becoming a Doctor--and a Mother   Front Page

ONCOLOGY Mutated Target Gives Potency to Lung Cancer Medication EGFR Abnormalities Predict Which Patients Respond In the beginning, gefitinib (Iressa) promised to become another successful smart drug, shutting down the activity of a cell surface receptor kinase that was abundant in lung tumors and seemed important for their survival. But the clinical trial results were disappointing, since gefitinib treatment gave no benefit to the majority of patients. The bright spot was the one in 10 patients who showed a dramatic improvement on the medication, with minimal side effects. Working in the lab and the clinic, researchers from Dana-Farber and Massachusetts General have independently identified a genetic alteration that leaves lung cancers open to attack by the targeted kinase inhibitor gefitinib. Leading the DFCI team were (from left) William Sellers, Matthew Meyerson, and Bruce Johnson (inset). The MGH group was headed by Daniel Haber (far right), shown with Kathryn Coser, supervisor of the DNA microarray core at MGH. (Photos by Steve Gilbert; Johnson courtesy of Bruce Johnson) The question of why gefitinib is spectacularly effective on 10 percent of lung cancers while leaving many untouched has now been answered by researchers from Massachusetts General Hospital and Dana-Farber Cancer Institute. Two research groups, one starting from clinical observations and the other from a high-capacity gene sequencing approach, have found that alterations in gefitinib's target, the epidermal growth factor receptor (EGFR), determine whether tumors will respond to the drug or not. The results may lead to rapid improvements in the treatment of lung cancer, the number one cancer killer in the United States. "The way Iressa is given now is not ideal. If we knew which patients had EGFR mutations, we could be smarter about it," said Daniel Haber, professor of medicine at MGH and senior author on a study that appeared online in The New England Journal of Medicine on April 29, ahead of a May 20 print date. Gefitinib may be used earlier in the patients carrying mutations, said Haber, rather than being held back as a last treatment option as it is now. "This work shows that mutations in solid tumors are every bit as important as they are in leukemia." --Daniel Haber Beyond lung cancer, the discovery that EGFR mutations define a drug-sensitive subset of cancers will spur the search for similar genetic changes in all kinds of other tumors. "These studies give strength to a general view of cancer treatment, which is the concept of targeted therapy and targeting mutations that are important for cancer growth," said Matthew Meyerson, HMS assistant professor of pathology at DFCI and a member of the Broad Institute at MIT and Harvard. Meyerson is a cosenior author on a paper that appeared simultaneously with the Haber report on April 29 in the online edition of Science and is expected to appear in a June print edition. The other senior authors include Bruce Johnson, HMS associate professor of medicine at Brigham and Women's Hospital, and William Sellers, HMS assistant professor of medicine at BWH and also of DFCI and the Broad Institute. Haber and Thomas Lynch, HMS associate professor of medicine at MGH, started to suspect a genetic lesion in the EGFR could underlie the response to gefitinib when they ran a clinical trial of the drug at MGH. After seeing no effect in most patients, they found a subset of 25 out of 275 treated who showed a dramatic response. They wondered whether changes in gefitinib's target might account for this difference, so the researchers isolated and sequenced the EGFR genes of nine responders and seven nonresponders. Eight of the nine responders had mutations in EGFR, compared with none of the nonresponders. The changes appeared to arise in the tumors, since none of the four patients they checked had mutations in normal tissue. When the researchers looked at tumors from 25 patients who had not been treated with gefitinib, they found that two of 25 (8 percent) had similar mutations, a number that was nearly the same as the overall response to gefitinib in clinical trials. Combing for Cancer Clues Meanwhile, Meyerson and Sellers were deep into a large-scale gene-sequencing project aimed at identifying new cancer targets by examining dozens of protein kinases from hundreds of tumor samples. After sequencing the EGFR from 119 lung cancers, Meyerson, Sellers, and their colleagues identified 16 tumors with mutations. They found that the EGFR changes showed up more often in tumors from nonsmoking women with adenocarcinoma and were more prevalent in tumors from a Japanese group than from American patients. This pattern closely followed the profile of patients who responded to gefitinib in clinical trials. "This was extremely exciting," said Sellers, and inspired the group to check the EGFR from nine lung cancer patients who had been treated with gefitinib at DFCI. Like their MGH colleagues, the DFCI researchers found EGFR mutations in all five responders and no changes in the four patients with resistant tumors. Both groups found identical or very similar mutations in EGFR from the gefitinib responders. Small deletions or substitutions cluster around the exact place that gefitinib binds in the altered EGFR. In cells, the altered EGFR was more active, which might explain how the mutations could spur tumor growth. Both groups found the mutated EGFR was also much more sensitive to inhibition by gefitinib. "The fact that two pieces of work started from different perspectives and came to the same conclusion really strengthens both studies," said Meyerson. Mutation Targets The new knowledge of how gefitinib fights tumors bolsters the gene-targeted approach to cancer therapy that blossomed after the success of the leukemia drug imatinib (Gleevec). "If you can identify a clear genetic lesion, you can attack that with smart drugs," said Meyerson. "We got great evidence of that from Gleevec, and this is additional evidence." Haber agrees. "This work shows that mutations in solid tumors are every bit as important as they are in leukemia." Because the mutations that predict gefitinib sensitivity are clustered in a small region of the EGFR gene, rapid genetic screening to tell doctors who should get gefitinib as a first-line treatment for lung cancer should be possible in a matter of months. But just as the mutation predicts which lung cancer patients will respond to gefitinib, it may also tell whether other tumors could be sensitive. So far, the MGH group has checked for EGFR mutations in 95 primary tumors and 108 cancer cell lines and found the changes only in lung cancers. The DFCI researchers are now sequencing the entire EGFR gene from nearly 1,000 tumors covering a wide variety of diseases. The gefitinib tale could become a case study in clinical drug development that encourages companies to take a good look at the genetic correlates of drug response, say several of the researchers. Given the dramatic benefit of gefitinib treatment for a subset of patients with EGFR mutations, it is worth remembering that gefitinib was considered a failure after its pivotal clinical trial. "Iressa almost didn't get approved. The trial reported a 10 percent partial response rate--that stinks," said Haber. "It was the dramatic nature of these responses that got the drug approved." --Pat McCaffrey