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

项目2：项目总结/摘要 在美国，去势抵抗性前列腺癌（CRPC）是男性癌症的第二大原因- 相关死亡。虽然有新的和高效的雄激素受体（AR）靶向治疗， 在转移性CRPC（例如恩杂鲁胺）的治疗中，大多数患者出现肿瘤耐药性。我们有 最近表明，在全身AR阻断的选择性压力下，肿瘤糖皮质激素受体（GR） 表达增加，GR活性维持促细胞存活基因表达，从而使CRPC 进展因此，GR活性在前列腺癌（PC）中的作用是动态和复杂的;最初，当 AR信号传导是完整的，GR激活似乎主要是抗增殖的，并且仅在随后的情况下， 持续的AR拮抗作用，GR信号传导是否有助于肿瘤进展。该项目的目标是 确定GR的促细胞存活活性如何随时间发展为AR激活状态的函数，以及 新的GR拮抗剂是否可以减轻GR活性从而降低恩杂鲁胺抗性（Enza-R）。 我们的中心假设是，治疗性AR阻断后，GR转录组从 主要是抗增殖基因表达的一个促进细胞存活。因此，我们预测， 增加百分比的Enza-RCRPC肿瘤细胞将显示显著的GR表达， 在GR拮抗作用的加入下经历细胞毒性。提出了三个目标来解决这个假设。 在目标1中，我们将分析GR转录功能在PC随着时间的推移之前，期间和之后AR封锁。在 目的2，我们将研究肿瘤内GR表达的异质性，以检验局灶性（克隆性） GR高表达区域逐渐表现出GR活化和恩杂鲁胺抗性。目标3是一种翻译 我们将在一项I期临床试验中研究一种新型SGRM与Enzalutamide联合治疗， Enza-R CRPC的治疗策略。此外，将在本试验背景下采集患者样本， 表征患者治疗前后循环肿瘤细胞（CTC）内AR和GR的表达 Enzalutamide和SGRM治疗。这项工作将有助于阐明GR激活的机制， 有助于PC进展，并将为阻断GR介导的促肿瘤发生信号传导提供信息 患者的路径。

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.