Mechanisms of Resistance to mTOR-Targeted Therapies

mTOR 靶向治疗的耐药机制

• 批准号: 8735575
• 负责人: JOSEPH F GERA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735575
• 关键词: Address; Adult; Animal Model; Antineoplastic Agents; Biochemical; Biogenesis; Cell Death; Cell Survival; Clinic; Complex; Data; Development; Disease; Drug Targeting; Drug resistance; Epidermal Growth Factor Receptor; Evaluation; Event; Family; Feedback; Future; Genetic; Genetic Translation; Glioblastoma; Growth Factor; Health; In Vitro; Internal Ribosome Entry Site; Intestinal Cancer; Lead; Link; MAPK11 gene; MAPK14 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Messenger RNA; Methodology; MicroRNAs; Molecular; Mutation; Nutrient; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Population; Preclinical Testing; Protein Biosynthesis; Protein Subunits; Protein Synthesis Inhibition; Proteins; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Reporting; Research; Resistance; Ribosomes; Role; Signal Transduction; Sirolimus; Structure-Activity Relationship; Testing; Therapeutic; Translation Initiation; Translations; Treatment Protocols; Veterans; cancer type; clinically relevant; clinically significant; hnRNP A1; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; mouse model; neoplastic cell; novel; outcome forecast; pre-clinical; preclinical study; research study; resistance mechanism; small molecule; tumor growth

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.

描述（由申请人提供）： 该提案的主要目标是研究肿瘤细胞对新开发的 mTOR 抑制剂耐药的内在机制，以便优化它们未来在临床中的使用。我们已经确定了一种 mRNA 翻译起始的替代机制，该机制在 mTOR 抑制剂暴露后被激活，使肿瘤细胞在蛋白质合成受到全面抑制的情况下仍能存活。这些实验将描述促进该挽救途径激活的信号事件，并将临床前评估一种针对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：我们将研究导致该挽救途径激活的分子事件，以及该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抵抗力的蛋白质。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：我们将结合遗传和生化方法来研究在 TOR 抑制剂耐药性脑癌中激活挽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功效。结果：这是一个新项目，尚未获得任何结果。临床意义：中枢神经系统恶性肿瘤在退伍军人中相对常见，目前的治疗方案尚未取得显着进展。开发额外的治疗方案可能会改善患者目前的预后，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可能会导致开发出治疗肠癌、肺癌和前列腺癌的其他治疗方案，这些癌症在我们的退伍军人群体中很常见。