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

糖皮质激素受体转录活性和恩杂鲁胺耐药 CRPC 的进化

• 批准号: 9752246
• 负责人: russell z szmulewitz
• 金额: $ 42.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752246
• 关键词: Address; Affect; Aftercare; Agonist; Androgen Receptor; Androgens; Apoptotic; Area; Biology; Cell Survival; Cessation of life; ChIP-seq; Clinical; Combined Modality Therapy; Complex; Coupled; DNA; Data; Development; Diffuse; Disease; Drug Kinetics; Evolution; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Heterogeneity; Hormones; Human; Immunofluorescence Immunologic; In Situ Hybridization; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Microdissection; Mifepristone; Neoplasm Circulating Cells; Nuclear; Palliative Care; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Prednisone; Progression-Free Survivals; Property; Proteins; RNA; Receptor Activation; Receptor Inhibition; Receptor Signaling; Reporting; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Steroid Receptors; Stress; Structure; Testing; Time; Transcriptional Activation; United States; United States Food and Drug Administration; Work; Xenograft procedure; androgen deprivation therapy; castration resistant prostate cancer; cytotoxicity; effective therapy; in vivo; male; neoplastic cell; novel; predictive marker; pressure; prostate cancer cell line; prostate cancer progression; receptor; receptor expression; receptor function; receptor upregulation; response; safety testing; targeted treatment; therapy resistant; transcriptome; transcriptome sequencing; treatment strategy; tumor; tumor heterogeneity; tumor progression; tumorigenic

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.

项目2：项目摘要/摘要 在美国，持cast割的前列腺癌（CRPC）是男性癌症的第二大原因 - 相关死亡。尽管有新的且高潜力的雄激素受体（AR）的靶向疗法 大多数患者的转移性CRPC治疗（例如恩扎拉酰胺），肿瘤耐药性会出现。我们有 最近表明，在全身性AR桶的选择性压力下，肿瘤糖皮质激素受体（GR） 表达增加，GR活性维持促核细胞存活基因表达，从而实现CRPC 进展。因此，GR活性在前列腺癌（PC）中的作用是动态且复杂的。最初 AR信号是完整的，GR激活似乎主要是抗增殖的，直到后来， 持续的AR拮抗作用确实有助于肿瘤进展。这个项目的目标是 确定GR的亲部生存活动的发展如何随着AR激活状态的函数，以及 新型的GR拮抗剂是否可以减轻GR活性，从而降低Enzalutamide-抗性（ENZA-R）。 我们的中心假设是，在治疗性AR阻断后，GR转录组从 主要是抗增殖的基因表达，以促进细胞存活。因此，我们预测 ENZA-R CRPC肿瘤细胞的百分比增加将表现出明显的GR表达，而GR表达将反过来 通过添加GR拮抗作用会经历细胞毒性。提出了三个目的来解决这一假设。 在AIM 1中，我们将随着AR封锁之前，期间和之后的时间分析PC中的GR转录功能。 AIM 2，我们将研究GR表达的肿瘤内异质性，以检验局灶性（克隆）的假设 AIM 3是翻译 目的我们将在I期临床试验中调查新的SGRM，并将其与enzalutamide结合 ENZA-R CRPC的治疗策略。此外，将在此试验的背景下收集患者样本 表征来自患者的循环肿瘤细胞（CTC）内和之后的AR和GR表达 用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的进展，并将为封锁GR介导的亲肿瘤信号传导的策略提供信息 患者的途径。