Glucocorticoid Receptor Transcriptional Activity and the Evolution of Enzalutamide-Resistant CRPC

项目2：项目摘要/摘要 在美国，耐阉割前列腺癌(CRPC)是男性癌症的第二大原因-- 相关死亡。虽然有新的和高度有效的雄激素受体(AR)靶向治疗 治疗转移性CRPC(如苯扎鲁胺)时，大多数患者会产生肿瘤耐药性。我们有 最近研究表明，在全身性AR阻断的选择性压力下，肿瘤糖皮质激素受体(GR) 表达增加和GR活性维持支持细胞生存的基因表达，从而使CRPC 进步。因此，GR活性在前列腺癌(PC)中的作用是动态和复杂的；最初 AR信号是完整的，GR激活似乎主要是抗增殖的，而且只是在晚些时候，在 持续的AR拮抗，GR信号是否有助于肿瘤的进展。这个项目的目标是 确定GR的促细胞存活活动如何随时间作为AR激活状态的函数而发展，以及 新型GR拮抗剂能否减轻GR活性，从而降低对苯扎鲁胺的耐药性(Enza-R)。 我们的中心假设是，在治疗性AR阻断后，GR转录组从 主要是抗增殖基因的表达，以促进细胞存活。因此，我们预测， Enza-R CRPC肿瘤细胞比例增加将表现出显著的GR表达，这反过来将 在加入受体GR拮抗剂的情况下进行细胞毒作用。针对这一假说，本文提出了三个目标。 在目标1中，我们将分析AR阻断前、中和之后PC中GR转录功能的变化。在……里面 目的2，我们将研究肿瘤内GR表达的异质性，以检验局部(克隆性) 进化的GR高表达区域表现出GR激活和对苯扎鲁胺的抗性。目标3是一部翻译版 目的：我们将在I期临床试验中研究一种新的SGRM，并将其与苯扎鲁胺联合作为一种 Enza-R CRPC的治疗策略。此外，将在本次试验的背景下收集患者样本，以 患者治疗前后外周血肿瘤细胞内AR和GR表达的特征 使用苯扎鲁胺和SGRM治疗。这项工作将有助于阐明GR激活的机制 有助于PC的进展，并将为阻断GR介导的促肿瘤信号提供策略 病人体内的路径。

PROJECT 2: PROJECT SUMMARY/ABSTRACT In the United States, castration-resistant prostate cancer (CRPC), is the second leading cause of male cancer- related deaths . Although there are new and highly potent androgen receptor (AR) targeted therapies for the treatment of metastatic CRPC (e.g. enzalutamide), tumor resistance develops in most patients. We have recently shown that under the selective pressure of systemic AR blockade, tumor glucocorticoid receptor (GR) expression increases and GR activity sustains pro-cell survival gene expression thereby enabling CRPC progression. The role of GR activity in prostate cancer (PC) is therefore dynamic and complex; initially when AR signaling is intact, GR activation appears to be mainly anti-proliferative and only later, in the context of sustained AR antagonism, does GR signaling contribute to tumor progression. The goal of this project is to determine how GR’s pro-cell survival activity develops over time as a function of AR activation state, and whether novel GR antagonists can mitigate GR activity thereby decreasing enzalutamide-resistance (Enza-R). Our central hypothesis is that following therapeutic AR blockade, the GR transcriptome shifts from predominantly anti-proliferative gene expression to one promoting cell survival. We therefore predict that an increasing percentage of Enza-R CRPC tumor cells will demonstrate significant GR expression that will in turn, undergo cytotoxicity with the addition ofr GR antagonism. Three aims are proposed to address this hypothesis. In Aim 1, we will analyze GR transcriptional function in PC over time before, during and after AR blockade. In Aim 2, we will investigate intratumoral heterogeneity of GR expression to test the hypothesis that focal (clonal) areas of high GR expression evolve exhibit GR-activation and enzalutamide resistance. Aim 3 is a translational aim in which we will investigate a novel SGRM in a phase I clinical trial in combination with enzalutamide as a treatment strategy for Enza-R CRPC. In addition, patient samples will be collected in the context of this trial to characterize AR and GR expression within circulating tumor cells (CTCs) from patients before and after treatment with enzalutamide and the SGRM. This work will help clarify the mechanisms by which GR activation contributes to PC progression and will inform strategies for blockade of GR-mediated pro-tumorigenic signaling pathways in patients.