Mechanisms of Resistance to mTOR Targeted Therapies

mTOR 靶向治疗的耐药机制

• 批准号: 10579603
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579603
• 关键词: Address; Adenosine; Adult; Animals; Arginine; Binding; Binding Sites; Biochemical; Biogenesis; Breast Cancer Model; Cell Survival; Clinic; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease model; Drug Targeting; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; FDA approved; FRAP1 gene; Feedback; Future; Genetic; Growth Factor; Holoenzymes; Hyperactivity; Internal Ribosome Entry Site; Link; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator; Messenger RNA; Methylation; Methyltransferase; Modification; Molecular; Mutation; Nutrient; Outcome; PI3K/AKT; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Population; Preclinical Testing; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Regulation; Reporting; Resistance; Ribosomes; Role; Signal Transduction; Sirolimus; Site; Testing; Transcript; Translation Initiation; Translations; Treatment Protocols; Veterans; antitumor effect; cancer drug resistance; cancer type; clinically actionable; clinically relevant; efficacy evaluation; evaluation/testing; experimental study; hnRNP A1; improved; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; mRNA Translation; mTOR Inhibitor; mTOR inhibition; malignant breast neoplasm; military veteran; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; patient prognosis; pre-clinical; preclinical study; resistance mechanism; small molecule inhibitor; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth

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 mechanisms by which the salvage protein synthesis pathway is activated in TOR inhibitor resistant brain and breast cancers. We will utilize mouse models of these diseases to evaluate the efficacy of these inhibitors.

这项提议的主要目的是研究肿瘤的内在机制。 细胞对新开发的mTOR抑制剂的抵抗力，使其未来的使用可能得到优化 在诊所里。我们已经确定了mRNA翻译启动的另一种机制，即 暴露mTOR抑制剂后激活，允许肿瘤细胞在全球 抑制蛋白质合成。这些实验将描绘出分子机制。 促进这一挽救途径的激活，并将在临床前评估 一种FDA批准的作为小分子抑制剂的药物，靶向于这一途径以实现协同作用 与mTOR抑制剂联合应用的抗肿瘤作用。我们将利用基因的组合 和生物化学方法来解决抢救蛋白质的机制 在耐TOR抑制剂的脑癌和乳腺癌中，合成途径被激活。我们会 利用这些疾病的小鼠模型来评估这些抑制剂的疗效。

项目成果

mTORC2 modulates feedback regulation of p38 MAPK activity via DUSP10/MKP5 to confer differential responses to PP242 in glioblastoma.

• DOI: 10.18632/genesandcancer.41
• 发表时间: 2014-11
• 期刊: Genes & cancer
• 作者: Benavides-Serrato A;Anderson L;Holmes B;Cloninger C;Artinian N;Bashir T;Gera J
• 通讯作者: Gera J

mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma.

• DOI: 10.1038/onc.2017.360
• 发表时间: 2018-02-08
• 期刊: Oncogene
• 影响因子: 8
• 作者: Holmes B;Benavides-Serrato A;Freeman RS;Landon KA;Bashir T;Nishimura RN;Gera J
• 通讯作者: Gera J