Pharmcogenomic dissection of mTOR translational targets in prostate cancer

前列腺癌 mTOR 翻译靶点的药物基因组解析

• 批准号: 8703036
• 负责人: Davide Ruggero
• 金额: $ 34.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703036
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Accounting; Active Sites; American; Animal Model; Apoptosis; Biological Markers; Cancer Etiology; Cell Cycle Arrest; Cessation of life; Clinical; Clinical Trials; Development; Dissection; Exhibits; Functional disorder; Future; Gene Expression; Genetic; Genomics; Goals; Grant; Human; Hyperactive behavior; Lead; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Molecular Genetics; Monitor; Mus; Oncogenic; Outcome; PTEN gene; Pathway interactions; Patients; Pharmacogenetics; Pharmacogenomics; Pharmacological Treatment; Phosphotransferases; Production; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; Reporter; Ribosomes; Role; Sampling; Signal Transduction; Sirolimus; Technology; Therapeutic; Time; Tissue Microarray; Translations; Treatment Efficacy; United States; cancer genome; cancer initiation; cancer therapy; cancer type; design; genome sequencing; genome-wide analysis; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; mTOR Inhibitor; mTOR inhibition; men; mouse model; neoplastic; new technology; novel; pre-clinical; preclinical study; prostate cancer cell; research study; response; therapeutic development; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the second most common cause of cancer-related death among men in the United States. The PI3K-AKT-mTOR pathway is highly deregulated in prostate cancer. An outstanding and poorly understood question is the contribution of the most downstream signaling components of this pathway, 4EBP-eIF4E and p70S6Ks that control gene expression at the translation level towards prostate cancer development. The significance of this question is underscored by the tremendous therapeutic potential for targeting downstream translational components of mTOR signaling in human cancer. In this proposal, we employ a novel pharmacogenomic approach that will allow us to delineate specific steps in protein synthesis control that impinge on post-genomic control of prostate cancer development and therapeutic response, which has not been previously possible due to a lack of appropriate genetic and molecular tools. Specifically, we have designed and validated in vivo animal models to functionally restore the activity of 4EBP-eIF4E, p70S6K1 and rpS6 to normal levels in the setting of oncogenic mTOR hyperactivation. Furthermore, we will use the first ATP active site inhibitors of mTOR, which we have developed and characterized, to pharmacologically interrogate the downstream translational components of mTOR in prostate cancer initiation, progression and therapeutic response. In the context of PTEN-mediated prostatic intraepithelial neoplasia (PIN), our preliminary findings show that these inhibitors exhibit the strongest effect on aberrant mTOR dependent protein synthesis known to date and lead to the complete regression of this neoplastic lesion. This is further substantiated by the ability of these inhibitors to induce cell cycle arrest and programmed cell death in human prostate cancer cells. In addition, we have successfully optimized and employed a novel technology for examining translation of the prostate cancer genome, known as ribosome profiling (RP). This led to the first functional genome-wide analysis of the translational state of prostate cancer modulated by oncogenic mTOR signaling, which lays the groundwork for experiments proposed in this grant. Together, our current proposal, which utilizes a convergence of state-of-the-art genetic mouse models, novel mTOR inhibitors, and translation profiling, will provide an unprecedented level of insight into the post-genomic mechanisms of prostate cancer development dictated at the level of protein synthesis control. Moreover, these studies will identify novel functional biomarkers for mTOR hyperactivity that may aid in predicting clinical outcomes as well as provide the preclinical rationale for targeting the most downstream translational components of mTOR signaling in human prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的第二大常见原因。 PI3K-AKT-mTOR 通路在前列腺癌中高度失调。一个突出且鲜为人知的问题是该通路的最下游信号成分、4EBP-eIF4E 和 p70S6K 在翻译水平上控制基因表达对前列腺癌发展的贡献。针对人类癌症中 mTOR 信号传导下游翻译成分的巨大治疗潜力强调了这个问题的重要性。在这项提案中，我们采用了一种新颖的药物基因组学方法，该方法将使我们能够描绘蛋白质合成控制中影响前列腺癌发展和治疗反应的基因组后控制的具体步骤，由于缺乏适当的遗传基因，这在以前是不可能的。和分子工具。具体来说，我们设计并验证了体内动物模型，以在致癌性 mTOR 过度激活的情况下将 4EBP-eIF4E、p70S6K1 和 rpS6 的活性功能性恢复至正常水平。此外，我们将使用我们开发并表征的第一个 mTOR ATP 活性位点抑制剂，从药理学角度探讨前列腺癌发生、进展和治疗反应中 mTOR 的下游翻译成分。在 PTEN 介导的前列腺上皮内瘤变 (PIN) 的背景下，我们的初步研究结果表明，这些抑制剂对迄今为止已知的异常 mTOR 依赖性蛋白质合成表现出最强的作用，并导致这种肿瘤病变的完全消退。这些抑制剂诱导人前列腺癌细胞细胞周期停滞和程序性细胞死亡的能力进一步证实了这一点。此外，我们还成功优化并采用了一种新技术来检查前列腺癌基因组的翻译，称为核糖体分析 (RP)。这导致了对致癌 mTOR 信号调节的前列腺癌翻译状态的首次功能性全基因组分析，这为本次资助中提出的实验奠定了基础。总之，我们当前的提案融合了最先进的基因小鼠模型、新型 mTOR 抑制剂和翻译分析，将为前列腺癌发展的后基因组机制提供前所未有的见解。蛋白质合成控制水平。此外，这些研究将确定 mTOR 过度活跃的新型功能性生物标志物，这些标志物可能有助于预测临床结果，并为针对人类前列腺癌中 mTOR 信号转导的最下游翻译组件提供临床前基本原理。