Nov. 24, 2008 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.
Heinrich is also a professor of medicine (hematology/medical oncology), OHSU School of Medicine.. The first paper is titled: "Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor."
Christopher Ryan, M.D., OHSU Knight Cancer Institute member and assistant professor of medicine (hematology/medical oncology), OHSU School of Medicine; and Charles Blanke, M.D., University of British Columbia, formerly at OHSU, also were authors on "Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group."
Pfizer Inc., the maker of Sutent, was one of the sponsors of this study through the Portland VA Research Foundation.
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