Mechanism/activity/resistance/Gleevec/GI stromal tumors (K23M)

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DESCRIPTION (provided by applicant): The objective of this grant proposal is to provide the candidate, Jonathan C. Trent, M.D., Ph.D., the experience, dedicated time, and training necessary to develop a career as an independent translational researcher in the study of sarcomas. Dr. Trent is a physician scientist with laboratory training in cancer biology and clinical training in sarcoma medical oncology. This award would allow him to focus 75% of his effort to career development and the proposed research. The incidence of gastrointestinal stromal tumors (GIST) is approximately 2000 to 5000 cases annually in the U.S. Until recently, advanced GIST has been a deadly disease that resists conventional cytotoxic cheomotherapy with response rates of 5% or less. The introduction of imatinib mesylate in 2000 dramatically changed the natural history of GISTs. Imatinib has been shown to have a response rate of 63% in a multicenter trial. Despite this remarkable result, approximately 37% of patients were refractory to imatinib and patients who initially responded are now relapsing. This study proposes an adjuvant imatinib trial for resected primary GISTs and a phase II study for patients with imatinib-resistant GIST. Both of these studies are designed with laboratory correlates designed to understand the mechanisms of action and resistance of imatinib in patients with GIST. Specific Aim 1: To determine the safety and efficacy of preoperative plus postoperative imatinib in patients with resectable, Kit-expressing GIST with laboratory correlates to investigate the mechanism of antitumor activity. Hypothesis: Imatinib's efficacy is due to induction of tumor cell apoptosis and inhibition of angiogenesis. Adjuvant imatinib therapy for patients with a completely resected GIST will improve disease free survival and overall survival. The use of microarray approaches will allow the precise identification of the genes responsible for response in GIST patients treated with imatinib mesylate. Specific Aim 2: To determine the safety and efficacy of antisense-Bcl-2 therapy in patients with imatinib-resistant, unresectable GIST with laboratory correlations to investigate the mechanism of resistance. Hypothesis: Resistance to imatinib is due to the anti-apoptotic protein Bcl-2 and antisense Bcl-2 therapy of patients with imatinib-resistant, advanced GIST will be an effective treatment. The use of microarray approaches will allow the precise identification of the genes responsible for resistance in GIST patients treated with imatinib mesylate. The study of GIST is an exciting opportunity for career development and to focus on the study of a disease that has been effectively treated by targeted therapy.