Activity & resistance of Gleevec in GI stromal tumors

描述(由申请人提供)：这项资助计划的目的是为候选人乔纳森·C·特伦特，医学博士，博士提供必要的经验、专门的时间和培训，以发展在肉瘤研究中的独立翻译研究人员的职业生涯。特伦特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内科肿瘤学临床培训。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(GIST)在美国每年的发病率约为2000-5000例。直到最近，晚期GIST一直是一种致命的疾病，对传统的细胞毒化疗有效率为5%或更低。2000年推出的甲磺酸伊马替尼极大地改变了GIST的自然历史。在一项多中心试验中，伊马替尼的有效率为63%。尽管有这个显著的结果，大约37%的患者对伊马替尼无效，最初有反应的患者现在正在复发。这项研究建议对切除的原发GIST进行伊马替尼佐剂试验，并对对伊马替尼耐药的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。 具体目的1：观察术前加术后伊马替尼在可切除肿瘤患者中的安全性和有效性，并与实验室检测结果进行相关性分析，探讨其抗肿瘤作用机制。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。对于完全切除的胃肠道间质瘤患者，辅以伊马替尼治疗将提高无病生存率和总生存率。微阵列方法的使用将使人们能够准确识别接受甲磺酸伊马替尼治疗的GIST患者的反应基因。 具体目的2：通过实验室对照研究反义Bcl2治疗对伊马替尼耐药、无法切除的胃肠道间质瘤的安全性和有效性，探讨耐药机制。假设：伊马替尼耐药是由于抗凋亡蛋白Bcl2和反义Bcl2治疗对伊马替尼耐药的患者，晚期GIST将是一种有效的治疗方法。微阵列方法的使用将使人们能够准确识别接受甲磺酸伊马替尼治疗的GIST患者的耐药基因。GIST的研究是职业发展的一个令人兴奋的机会，并将重点放在通过靶向治疗有效治疗的疾病的研究上。

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.