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

描述（由申请人提供）：本赠款提案的目的是提供候选人，乔纳森C。 特伦特医学博士哲学博士、经验，专门的时间，和必要的培训，以发展职业生涯作为一个独立的翻译研究人员在肉瘤的研究。 Trent博士是一名内科科学家，接受过癌症生物学实验室培训和肉瘤医学肿瘤学临床培训。 这一奖项将使他能够将75%的精力集中在职业发展和拟议的研究上。 胃肠道间质瘤（gastrointestinal stromal tumor，GIST）的发病率在美国每年约为2000 ~ 5000例。晚期GIST是一种致命的疾病，对传统的细胞毒性化疗有抵抗力，其缓解率为5%或更低。 伊马替尼在多中心试验中的反应率为63%。 尽管有这个显著的结果，大约37%的患者对伊马替尼难治，最初有反应的患者现在复发了。 本研究提出了一项伊马替尼辅助治疗原发性胃肠道间质瘤的临床试验和一项伊马替尼耐药胃肠道间质瘤患者的II期临床研究。 这两项研究均采用实验室相关性设计，旨在了解伊马替尼在GIST患者中的作用机制和耐药性。 具体目标1：确定术前加术后伊马替尼在可切除、表达Kit的GIST患者中的安全性和有效性，实验室相关性研究抗肿瘤活性的机制。 假设：伊马替尼的疗效是由于诱导肿瘤细胞凋亡和抑制血管生成。 辅助伊马替尼治疗完全切除的GIST患者将提高无病生存期和总生存期。 微阵列方法的使用将允许精确鉴定负责用甲磺酸伊马替尼治疗的GIST患者的反应的基因。 具体目标二：确定反义Bcl-2治疗对伊马替尼耐药、不可切除的GIST患者的安全性和有效性，并进行实验室相关性研究，以探讨耐药机制。 假设：伊马替尼耐药是由于抗凋亡蛋白Bcl-2和反义Bcl-2治疗伊马替尼耐药的患者，将是晚期GIST的有效治疗方法。 微阵列方法的使用将允许精确鉴定用甲磺酸伊马替尼治疗的GIST患者中负责耐药的基因。 GIST的研究是职业发展的一个令人兴奋的机会，并专注于研究一种已通过靶向治疗有效治疗的疾病。

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.