Activity & resistance of Gleevec in GI stromal tumors

描述（由申请人提供）：本资助提案的目的是为候选人Jonathan C. Trent, m.d., Ph.D.，提供必要的经验，投入的时间和培训，以发展成为肉瘤研究的独立转化研究人员。Trent博士是一名内科科学家，接受过癌症生物学的实验室培训和肉瘤医学肿瘤学的临床培训。该奖项将使他能够将75%的精力集中在职业发展和拟议的研究上。在美国，胃肠道间质瘤（GIST）的发病率每年约为2000至5000例。直到最近，晚期胃肠道间质瘤一直是一种致命的疾病，对传统的细胞毒性化疗有抵抗作用，反应率为5%或更低。2000年甲磺酸伊马替尼的引入极大地改变了gist的自然历史。在一项多中心试验中，伊马替尼的反应率为63%。尽管这个显著的结果，大约37%的患者对伊马替尼难治，最初有反应的患者现在又复发了。本研究提出对切除的原发性GIST进行伊马替尼辅助试验，并对伊马替尼耐药GIST患者进行II期研究。这两项研究都设计了实验室相关性，旨在了解伊马替尼在GIST患者中的作用机制和耐药性。

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.