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

基本信息

批准号：
8919267
负责人：
Davide Ruggero
金额：
$ 35.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919267
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

项目摘要

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与癌症相关死亡的第二大原因。 PI3K-AKT-MTOR途径在前列腺癌中受到高度失调。一个杰出且知之甚少的问题是该途径，4EBP-EIF4E和P70S6K的最下游信号传导成分的贡献，这些途径在翻译水平上控制基因表达对前列腺癌发展的贡献。这个问题的重要性是由靶向人类癌症中MTOR信号的下游翻译成分的巨大治疗潜力的强调。在此提案中，我们采用了一种新型的药物基因组方法，该方法将使我们能够描述蛋白质合成控制中的特定步骤，这些步骤影响了前列腺癌发展后的基因组控制和治疗反应，由于缺乏适当的遗传学和分子工具，因此以前无法使用。具体而言，我们已经设计和验证了体内动物模型，以恢复在致癌MTOR过度激活的情况下，在功能上恢复4EBP-EIF4E，P70S6K1和RPS6的活性。此外，我们将使用我们已经开发和表征的MTOR的第一个ATP活性位点抑制剂，以在药理学上询问MTOR在前列腺癌的开始，进展和治疗反应中的下游转化成分。在PTEN介导的前列腺上皮内肿瘤（PIN）的背景下，我们的初步发现表明，这些抑制剂对已知已知的MTOR依赖性蛋白质合成具有最强的作用，并导致这种肿瘤性病变的完全回归。这些抑制剂在人前列腺癌细胞中诱导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，我们已经成功地优化并采用了一种新技术来检查前列腺癌基因组的翻译，即核糖体分析（RP）。这导致了通过致癌MTOR信号调节的前列腺癌转化状态的首次功能性基因组分析，这为本赠款中提出的实验奠定了基础。我们当前的提案一起利用了最先进的遗传小鼠模型，新型MTOR抑制剂和翻译分析的收敛性，将提供对前列腺癌后发展机制的前所未有的见解，在蛋白质合成控制水平上决定了前列腺癌的发展。此外，这些研究将确定用于MTOR多动症的新型功能生物标志物，这可能有助于预测临床结果，并为靶向人类前列腺癌中MTOR信号的最下游翻译成分提供了临床前原理。