OHSU Knight Cancer Institute researcher: study may result in more targeted drugs for GISTNovember 13, 2008PORTLAND, Ore. - According to Oregon Health & Science University Knight Cancer Institute researchers, there is strong evidence that patients can have varying clinical responses to medications depending on the specific makeup of their cancer. The study, which focused on, gastrointestinal stromal tumors, also called GIST, found that the genetic variations in their disease appear to determine which medications will be most effective. "What these findings mean is that we can begin to develop an individualized approach to the treatment of GIST. We can tailor therapy based on the genetic makeup of the tumor," said Michael Heinrich, M.D., interim head of hematology/medical oncology, and section chief of hematology /medical oncology, Portland Veterans Affairs Medical Center. Heinrich is co-author with Christopher Corless, M.D., Ph.D., vice chairman for research and professor of pathology and OHSU Knight Cancer Institute member. The data was published in two papers in the Journal of Clinical Oncology. The journal also published an editorial about this research. Gleevec, (imatinib), the FDA-approved first line of treatment for GIST, was initially developed by OHSU Knight Cancer Institute Director Brian Druker, M.D., to treat chronic myeloid leukemia. Heinrich further pioneered the use of Gleevec for GIST. In GIST, Gleevec targets mutations of the KIT or PDGFRA enzymes KIT mutations are found in 80 percent to 85 percent of tumors; PDGFRA mutations are found in about 5percent of tumors; and no mutations of KIT or PDGFRA are found in 10 percent to 15 percent of tumors, so called wild-type tumors. In the first study, Heinrich analyzed tumor specimens from almost 400 GIST patients who were treated with Gleevec. The presence and type of mutation predicted their response to Gleevec: patients with a certain type of KIT mutation -- KIT exon 11, which is present in 70 percent of GIST patients -- had the best response to Gleevec, followed by wild-type GISTs, and then GIST with KIT exon 9 mutations. In addition, evidence indicates that patients with exon 9-mutant GIST did better if they receive double the usual daily dose of Gleevec. In contrast, patients with other types of GIST, do equally well on the standard daily dose of Gleevec. Although the vast majority of GISTs respond well to Gleevec treatment, over time tumors can become resistant and regrow. To combat this problem, a second drug, Sutent (sunitinib), was tested in clinical studies and shown to be active in treating Gleevec-resistant GIST. Like Gleevec, Sutent targets KIT and PDGFRA enzymes. However, unlike Gleevec, Sutent can also block blood vessel formation in GISTs. To better understand how Sutent works, Heinrich's team analyzed tumor samples from 78 subjects treated with Sutent as part of a phase I/II clinical study. These results were reported in a second article in the journal. Notably, trial participants whose tumors have KIT exon 9-mutations or wild-type tumors, had better survival during Sutent treatment, when compared with patients whose tumors had KIT exon 11-mutant tumors. Using laboratory methods, Heinrich's team found that Sutent was more potent than Gleevec for inhibiting the aberrant KIT enzyme activity in KIT exon 9-mutant and wild-type tumors. In addition, Heinrich's team found that a common cause of Gleevec-resistance in GIST is the development of new mutations that block the ability of Gleevec to inhibit the rogue KIT enzyme. In a test tube system, Sutent can inhibit some but not all of these resistance mutations. "In GIST the KIT enzyme acts like a car motor that is stuck running at full speed. Gleevec acts like a key that allows the motor to be turned off. Unfortunately, over time, GIST cells can further change the lock by mutating, so that Gleevec can't turn off the motor. Sutent is a different kind of key that can work on some Gleevec-resistant tumors. But it only works on some secondary mutations. We need other keys, or other drugs, to attack all of the possible resistance mutations," Heinrich said. "We knew that Sutent worked, but these results help show us why it works. These early data show that there are differences in how certain mutations and genes respond to therapy. By finding the original defect, we can predict better an individual tumor's response to Sutent." Heinrich said that larger studies are needed to confirm these results, as well as better, quicker testing methods for these gene mutations. Oregon Health & Science University |
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| Related GIST Current Events and GIST News Articles Scripps team shows diet switching can activate brain's stress system, lead to 'withdrawal' symptoms In research that sheds light on the perils of yo-yo dieting and repeated bouts of sugar-bingeing, researchers from The Scripps Research Institute have shown in animal models that cycling between periods of eating sweet and regular-tasting food can activate the brain's stress system and generate overeating, anxiety, and withdrawal-like symptoms. Study finds survival rates from gastrointestinal tumors improving among African-Americans New research published in the July issue of the Journal of the American College of Surgeons reveals that African Americans with gastrointestinal stromal tumors (GIST), a rare cancer that begins in the wall of the gastrointestinal tract, now have survival rates equivalent to those of Caucasians. Gene signature may predict patient response to therapy for gastrointestinal stromal tumors Researchers at Fox Chase Cancer Center uncovered a genetic pattern that may help predict how gastrointestinal stromal tumor (GIST) patients respond to the targeted therapy imatinib mesylate (Gleevec). Research ties tree mortality trends to climate warming Global warming is speeding up the mortality of trees, and NAU research is providing some of the data to prove it. Deal or No Deal? The Role of Emotions in Negotiating Offers We all negotiate compromises every day, but it often seems that certain people always get their way. Do these skilled negotiators simply go with their gut instinct every time or are they just extremely calculating, figuring out all possible outcomes before settling on the best option? UC Davis research could lead to no scent, no sex for the Japanese beetle If a male Japanese beetle is unable to detect the sex pheromone released by a female, he won't be able to locate her and reproduce. OHSU Cancer Instutute researchers find abnormalities in gene for melanoma New research from the Oregon Health & Science University Cancer Institute about mutations in melanoma may bring a wellspring of hope to many patients. Memory on Trial The U.S. legal system has long assumed that all testimony is not equally credible, that some witnesses are more reliable than others. In tough cases with child witnesses, it assumes adult witnesses to be more reliable. But what if the legal system had it wrong? Nanotube-producing bacteria show manufacturing promise Two engineers at the University of California, Riverside are part of a binational team that has found semiconducting nanotubes produced by living bacteria - a discovery that could help in the creation of a new generation of nanoelectronic devices. Mineral ages show Blue Mountain rocks related to Klamath, Sierra Nevadas New evidence, based on mineral dating, suggests that rocks of the Blue Mountains, the oldest geological formation in Oregon, may have been derived from the Klamath and Sierra Nevada mountain chains, University of Oregon researchers report. More GIST Current Events and GIST News Articles |
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