Molecular Mechanisms in Gastrointestinal Stromal Tumor

描述(申请人提供)：胃肠道间质瘤(GIST)是最常见的肠道间充质肿瘤。直到最近，手术一直是GIST患者唯一有效的治疗方法。尽管肿瘤被完全切除，但大多数患者会发展为复发疾病，并最终死于复发疾病。大多数GIST具有KIT原癌基因功能突变的获得性，导致KIT结构性蛋白激活和细胞增殖失控。STI571是一种小分子，它选择性地抑制KIT和其他一些酪氨酸激酶。它代表了癌症治疗领域的一项里程碑式的成就。STI571证实了分子肿瘤学领域的有效性，因为它证明了一种特定的抑制物可以用于靶向导致肿瘤发病机制的分子异常。STI571对大约三分之二的转移性胃肠道间质瘤患者有效。接受手术切除的原发GIST患者可以受益于辅助剂STI571，这是正在进行的CTEP赞助的第三阶段随机、双盲、安慰剂对照组间试验的主题。我们建议对从参加多中心试验的患者收集的组织标本进行研究。我们假设，原发性GIST的分子特征可以预测辅助性STI571治疗后的临床结果。此外，我们推测，复发GIST的后续分子变化将揭示GIST中STI571耐药的机制。在目标1中，我们将把原发GIST的特殊病理(肿瘤部位和大小)和细胞遗传学(5p、17q或20q的增加或9p的丢失)表型与复发和生存联系起来。目的探讨原发性胃肠道间质瘤KIT基因突变状态与复发和生存的关系。在目标3中，我们将比较原发和复发GIST的病理和分子特征，以开始确定STI571耐药的分子机制。拟议中的实验代表了首次对原发GIST进行前瞻性的临床和病理学研究，并将揭示GIST(安慰剂ARM)的自然历史以及辅助治疗(STI571 ARM)的反应。这些数据将为未来原发GIST的临床病理研究设定标准，并可能为治疗对STI571产生耐药性的GIST患者提供方法。这一结果将进一步定义GIST生物学，并适用于其他使用分子药物治疗的疾病。

DESCRIPTION (provided by applicant): Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the intestinal tract. Until recently, surgery has been the only effective therapy for patients with GIST. Despite complete resection of their tumor, most patients develop, and eventually die from, recurrent disease. The majority of GISTs possess a gain of function mutation in the KIT proto-oncogene resulting in constitutive KIT protein activation and uncontrolled cell proliferation. STI571 is a small molecule that selectively inhibits KIT and a few other tyrosine kinases. It represents a landmark achievement in cancer therapeutics. STI571 validates the field of molecular oncology as it proves that a specific inhibitor can be used to target a molecular aberration responsible for the pathogenesis of neoplasia. STI571 is effective in about two-thirds of patients with metastatic GIST. Patients with primary GIST who undergo surgical resection may benefit from adjuvant STI571 and this is the subject of an ongoing CTEP sponsored Phase III randomized, double blind, placebo controlled, intergroup trial. We propose to study the tissue specimens collected from the patients enrolled in the multicenter trial. We hypothesize that the molecular characteristics of primary GIST predict the clinical outcome after adjuvant STI571 therapy. Furthermore, we postulate that subsequent molecular changes in recurrent GIST will reveal the mechanism of STI571 resistance in GIST. In Aim 1, we will correlate specific pathologic (tumor site and size) and cytogenetic (gains of 5p, 17q, or 20q or loss of 9p) phenotype of primary GIST to recurrence and survival. Aim 2 focuses on the relationship of KIT mutation status of primary GIST to recurrence and survival. In Aim 3, we will compare the pathologic and molecular features of primary GIST to recurrent GIST to begin to define the molecular mechanisms of STI571 resistance. The proposed experiments represent the first prospective clinical and pathologic study of primary GIST and will reveal the natural history of GIST (placebo arm) as well as the response to an adjuvant therapy (STI571 arm). The data will set the standard for future clinicopathologic studies in primary GIST and may provide approaches to treat patients with GIST who become resistant to STI571. The results will further define GIST biology and be applicable to other diseases treated with molecular agents.