Mechanisms of Resistance to mTOR-Targeted Therapies

mTOR 靶向治疗的耐药机制

• 批准号: 8974387
• 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/8974387
• 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; FRAP1 gene; Family; Feedback; Future; Genetic; Genetic Translation; Glioblastoma; Growth; 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; 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; antitumor effect; cancer type; clinically actionable; clinically relevant; clinically significant; hnRNP A1; improved; in vivo; inhibitor/antagonist; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; outcome forecast; pre-clinical; preclinical study; public health relevance; research study; resistance mechanism; small molecule; small molecule inhibitor; targeted treatment; 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）： 该提案的广泛目的是研究肿瘤细胞对新开发的MTOR抑制剂的抗内部机制，以便在诊所中可以优化其未来使用。我们已经确定了mRNA翻译起始的替代机制，该机制在MTOR抑制剂暴露时被激活，允许面对蛋白质合成的全球抑制作用，允许肿瘤细胞存活。这些实验将描述促进该打捞途径激活的信号传导事件，并将链式链接地评估一种针对该途径的新型小分子抑制剂，以与MTOR抑制剂结合使用该途径来协同抗肿瘤作用。研究计划：我们将研究导致这种打捞途径激活的分子事件，以及该信号级联对细胞平移机械的撞击如何损害了特异性合成蛋白质赋予肿瘤细胞耐药性的蛋白质。此外，我们将在与直接MTOR激酶抑制剂的共同处理研究中评估该途径的新型抑制剂。方法论：我们将利用遗传和生化方法的结合来解决在TOR抑制剂抗脑癌中激活打捞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，尚未获得结果。临床意义：中枢神经系统恶性肿瘤在我们的退伍军人中相对频繁遇到，目前的治疗方案并未显着提高。额外治疗选择的发展可能会改善患者目前的预后，这仍然是10个月的惨淡。了解对恶性胶质母细胞瘤的治疗可能会导致在我们的退伍军人人群中常见的肠，肺和前列腺癌的其他治疗选择。