Mechanisms of Resistance to mTOR Targeted Therapies

mTOR 靶向治疗的耐药机制

基本信息

批准号：
10266024
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266024
关键词：
Address Adult Animals Arginine Biochemical Biogenesis Cancer Model Cell Death Cell Survival Clinic Complex Data Development Disease model Docking Drug Targeting Drug resistance Epidermal Growth Factor Receptor Evaluation FDA approved FRAP1 gene Feedback Future Genetic Genetic Transcription Genetic Translation Glioblastoma Growth Factor In Vitro Internal Ribosome Entry Site Intestinal Cancer Lead Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Mediator of activation protein Messenger RNA Methylation Methyltransferase Modification Molecular Mutation Nutrient PI3K/AKT PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Preclinical Testing Prognosis Protein Biosynthesis Protein Synthesis Inhibition Proteins Proto-Oncogene Proteins c-akt RNA methylation Receptor Protein-Tyrosine Kinases Recurrence Regulation Reporting Resistance Ribosomes Riluzole Role Signal Transduction Sirolimus Site Testing Therapeutic Transcript Translation Initiation Translations Treatment Protocols Veterans antitumor effect cancer drug resistance cancer therapy cancer type clinically actionable clinically relevant efficacy evaluation experimental study hnRNP A1 improved in vivo inhibitor/antagonist kinase inhibitor mTOR Inhibitor mTOR inhibition military veteran mouse model neoplastic cell new therapeutic target novel novel therapeutics pre-clinical preclinical study resistance mechanism small molecule inhibitor synergism targeted treatment tumor growth

项目摘要

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 molecular mechanisms promoting activation of this salvage pathway and will pre-clinically evaluate the repurposing of an FDA-approved drug as a small molecule inhibitor targeting this pathway for synergistic antitumor effects in combination with mTOR inhibitors. 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.

该提案的广泛目标是研究肿瘤的内在机制细胞对新开发的 mTOR 抑制剂产生耐药性，以便优化其未来的使用在诊所里。我们已经确定了 mRNA 翻译起始的另一种机制，即 mTOR 抑制剂暴露后激活，使肿瘤细胞能够在全球环境中生存抑制蛋白质合成。这些实验将描述分子机制促进该挽救途径的激活，并将进行临床前评估 FDA 批准的药物作为小分子抑制剂，针对该途径产生协同作用与 mTOR 抑制剂联合使用具有抗肿瘤作用。我们将利用基因组合和生化方法来解决抢救的分子机制 TOR 抑制剂耐药性脑癌中蛋白质合成途径被激活。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。