Hormone signaling and translation control in advanced prostate cancer

项目摘要/摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 20-014.最近出现的雄激素受体和雄激素生物合成的高效抑制剂 有不幸的医源性作用，助长了患者新的致命前列腺癌表型。特别是， 对苯扎鲁胺和阿比特龙等治疗耐药的去势抵抗前列腺癌(CRPC) 在患者中的发生率正在增加，并且一致是致命的。阻碍治疗的主要障碍 进展是缺乏相关的疾病模型，而且对导致 上升到这种表型。长期以来，蛋白质的合成过程一直被认为从属于蛋白质的变化 DNA和RNA水平在肿瘤病因学中的作用然而，我们实验室和其他实验室的工作表明， 蛋白质合成调控是一个动态的过程，它不仅协调大量的mRNA翻译，而且还协调 对癌症表型很重要的不同mRNAs的专门翻译。 最近，我们的实验室发现了雄激素受体信号和雄激素受体之间的新的功能联系。 信使核糖核酸翻译起始过程。我们发现雄激素受体活性的降低会导致 驱动激素信号转导的eIF4F翻译起始复合体活性的补偿性增加 在CRPC中的独立性。重要的是，这是通过翻译不同的mRNAs亚集来调节的。 基于这些发现，我们假设不同基因网络的异常mrna翻译能够 对核激素受体抑制和CRPC进展的抵抗。我们的长期目标是利用 最先进的患者衍生模型、核糖体分析和下一代翻译抑制剂 明确地研究雄激素受体和蛋白质合成控制之间的基本联系 前列腺癌患者的高度相关性和新出现的病程。要做到这一点，我们将解决 目的如下：1)确定mRNA翻译启动的改变如何促进对AR途径的抵抗 定向治疗，以及2)描述促进对AR信号耐药的翻译基因网络 抑制剂。 最终，这些研究将揭示核激素受体基因调控的新范式。 并为靶向蛋白质合成装置提供临床前基础。 越来越常见和高度侵袭性的疾病。

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 20-014. The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, castration resistant prostate cancer (CRPC) that is resistant to therapies such as enzalutamide and abiraterone are increasing in occurrence amongst patients and is uniformly fatal. The main barriers against therapeutic advances are a paucity of relevant disease models and a very poor understanding of the mechanisms that give rise to this phenotype. The process of protein synthesis has long been considered subordinate to alterations at the levels of DNA and RNA in cancer etiology. However, work from our laboratory and others have revealed that protein synthesis control is a dynamic process that coordinates not only bulk mRNA translation, but also the specialized translation of distinct mRNAs important for cancer phenotypes. Recently, our laboratory has uncovered a new functional link between androgen receptor signaling and the process of mRNA translation initiation. We found that decreases in androgen receptor activity lead to a compensatory increase in the activity of the eIF4F translation initiation complex which drives hormone signaling independence in CRPC. Importantly, this is mediated through the translation of distinct subsets of mRNAs. Based on these findings, we hypothesize that aberrant mRNA translation of distinct gene networks enables resistance to nuclear hormone receptor inhibition and CRPC progression. Our long-term objective is to utilize state-of-the-art patient derived models, ribosome profiling, and next-generation translation inhibitors to definitively investigate the fundamental link between the androgen receptor and protein synthesis control in a highly relevant and newly emerging disease course for prostate cancer patients. To do so, we will address the following aims: 1) determine how alterations in mRNA translation initiation promote resistance to AR pathway directed therapies, and 2) delineate the translational gene networks that promote resistance to AR signaling inhibitors. Ultimately, these studies are poised to uncover a new paradigm for gene regulation in nuclear hormone receptor inhibitor resistance and provide the preclinical basis for targeting the protein synthesis apparatus in an increasingly common and highly aggressive disease.