Mechanisms of Resistance to mTOR-Targeted Therapies

描述(由申请人提供)： 这项建议的主要目的是研究肿瘤细胞对新开发的mTOR抑制剂耐药的内在机制，以便将来在临床上优化其使用。我们已经确定了另一种启动mRNA翻译的机制，这种机制在暴露mTOR抑制剂时激活，允许肿瘤细胞在蛋白质合成受到全球抑制的情况下存活。这些实验将描述促进这一挽救途径激活的信号事件，并将在临床前评估针对这一途径的新型小分子抑制剂与mTOR抑制剂联合应用的协同抗肿瘤作用。研究计划：我们将研究导致这一挽救途径激活的分子事件，以及这一信号级联如何影响细胞翻译机制，从而特异性地合成与肿瘤细胞耐药相关的蛋白质。此外，在与直接mTOR激酶抑制剂的联合治疗研究中，我们将评估该途径的一种新的抑制剂的协同抗肿瘤效果。方法：我们将利用遗传和生化方法的组合来解决TOR抑制剂耐药脑癌中挽救蛋白合成途径被激活的分子机制。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：这是一个新的项目，尚未取得任何成果。临床意义：中枢神经系统恶性肿瘤在退伍军人中相对常见，目前的治疗方案并未取得显着进展。开发更多的治疗方案可能会改善目前患者的预后，目前患者的预后仍处于令人沮丧的10个月。了解恶性胶质母细胞瘤的治疗方法可能会导致开发其他治疗方案来治疗肠癌、肺癌和前列腺癌，这些癌症在我们的退伍军人中很常见。

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.