Project 1: Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell Proliferation and Survival

自前列腺癌（PCa）抑制雄激素受体（AR）的临床工作开始以来 通过减少AR配体（雄激素剥夺疗法，ADT）进行信号传导， 对ADT（去势抵抗性前列腺增生）后复发的男性给予睾酮（T） 癌症，CRPC）可能导致实质性的临床反应。然而，这些报告主要是 轶事和缓解是高度可变的。相比之下，来自临床前模型的丰富数据 可重复地显示出对肿瘤敏感的癌症的双相反应， 浓度诱导增殖，但在更高的超生理雄激素（SPA）浓度下， 增殖受到抑制，并且在某些情况下参与了凋亡程序。虽然常常 被认为是一种临床意义不大的体外现象，最近严格控制的临床 SPA的试验在CRPC男性亚组中产生了实质性的临床反应。总的来说，这些 研究结果支持旨在确定驱动这些反应的分子机制的研究。 基于迄今为止的这些临床前和临床发现，我们假设基因组和 有助于CRPC进展的表观基因组适应性过程也使肿瘤细胞对CRPC敏感。 在SPA条件下由AR调节的分化、静止和凋亡程序。我们将 通过三个相互关联的目标来测试这个假设：目标1。确定主要机制， SPA抑制CRPC。AIM 2.定义SPA重编程的前列腺癌中的AR顺式组， 鉴定SPA效应所必需或抑制SPA效应的协同基因和途径。AIM 3. 确定与SPA协同作用的药物组合，以抑制肿瘤生长并优化 基于SPA介导的生长停滞的机制理解的AR激动。

Since the inception of clinical efforts in prostate cancer (PCa) to suppress androgen receptor (AR) signaling by reducing AR ligands (androgen deprivation therapy, ADT), it was recognized that the administration of testosterone (T) to men who have relapsed after ADT (castration-resistant prostate cancer, CRPC) could result in substantial clinical responses. However, these reports were largely anecdotal and remissions were highly variable. In contrast, abundant data from preclinical models have reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T concentrations proliferation is induced, but at higher, supraphysiological androgen (SPA) concentrations, proliferation is suppressed and in some instances apoptotic programs are engaged. Though often considered to be an in vitro phenomenon of little clinical importance, recent rigorously controlled clinical trials of SPA produced substantial clinical responses in subsets of men with CRPC. Collectively, these findings support studies designed to determine the molecular mechanism(s) driving these responses. Based on these preclinical and clinical findings to date, we hypothesize that the genomic and epigenomic adaptive processes that contribute to CRPC progression also sensitize tumor cells to the differentiation, quiescence and apoptotic programs regulated by the AR under conditions of SPA. We will test this hypothesis through three linked aims: AIM 1. Determine the primary mechanism(s) by which SPA represses CRPC. AIM 2. Define the AR cistrome in prostate cancers reprogrammed by SPA and identify cooperating genes and pathways that are essential or suppressive of SPA effects. AIM 3. Identify drug combinations that synergize with SPA to repress tumor growth and optimize the effects of AR agonism based on a mechanistic understanding of SPA-mediated growth arrest.