Mechanisms of Resistance to mTOR-Targeted Therapies

描述（由申请人提供）： 该提案的主要目的是研究肿瘤细胞对新开发的mTOR抑制剂耐药性的内在机制，以便在临床中优化其未来的使用。我们已经确定了mRNA翻译起始的替代机制，其在mTOR抑制剂暴露后被激活，从而允许肿瘤细胞在蛋白质合成的整体抑制下存活。这些实验将描述促进该挽救途径活化的信号传导事件，并将临床前评估靶向该途径的新型小分子抑制剂与mTOR抑制剂组合的协同抗肿瘤作用。研究计划：我们将研究导致这种补救途径激活的分子事件，以及这种信号级联如何影响细胞翻译机制，以特异性合成赋予肿瘤细胞抗性的蛋白质。此外，我们将在与直接mTOR激酶抑制剂的联合治疗研究中评估该途径的新型抑制剂的协同抗肿瘤作用。方法学：我们将利用遗传学和生物化学方法的组合来解决在TOR抑制剂抗性脑癌中激活补救蛋白合成途径的分子机制。我们将利用这些疾病的小鼠模型来评估这些抑制剂的疗效。结果：这是一个新项目，尚未获得结果。临床意义：CNS恶性肿瘤在我们的退伍军人中相对常见，目前的治疗方案尚未显着进展。其他治疗方案的开发可能会改善患者目前的预后，目前的预后仍然是令人沮丧的10个月。了解恶性胶质母细胞瘤的治疗可能会导致开发用于治疗肠癌，肺癌和前列腺癌的其他治疗选择，这些癌症在我们的退伍军人群体中很常见。

DESCRIPTION (provided by applicant): The broad objective of this proposal is to investigate the intrinsic mechanisms of tumor cell resistance to newly developed mTOR inhibitors such that their future use may be optimized in the clinic. We have identified an alternate mechanism of mRNA translation initiation that is activated upon mTOR inhibitor exposure allowing tumor cell survival in the face of global inhibition of protein synthesis. These experiments will delineate the signaling events promoting activation of this salvage pathway and will pre-clinically evaluate a novel small molecule inhibito targeting this pathway for synergistic antitumor effects in combination with mTOR inhibitors. Research Plan: We will investigate the molecular events leading to activation of this salvage pathway, as well as how this signaling cascade impinges on the cellular translational machinery to specifically synthesize proteins conferring tumor cell resistance. Additionally, we will evaluat a novel inhibitor of this pathway for synergistic antitumor effects in co-treatment studies with direct mTOR kinase inhibitors. Methodology: We will utilize a combination of genetic and biochemical approaches to address the molecular mechanisms by which the salvage protein synthesis pathway is activated in TOR inhibitor resistant brain cancers. We will utilize mouse models of these diseases to evaluate the efficacy of these inhibitors. Results: This is a new project and no results have been obtained. Clinical Significance: CNS malignancies are relatively frequently encountered in our Veterans and current treatment protocols have not advanced significantly. The development of additional treatment options may improve the current prognosis for patients, which remains at a dismal 10 months. Understanding the treatment of malignant glioblastomas may lead to the development of additional therapeutic options for the treatment of bowel, lung and prostate cancers, which are common in our Veteran population.