Androgen Receptor Action in Castration Resistant Prostate Cancer

描述(申请人提供)：过去几年见证了前列腺癌(PCA)治疗的范式转变；现在人们普遍接受雄激素受体(AR)仍然活跃，是手术或药物去势后复发的前列腺癌(去势耐受前列腺癌，CRPC)的治疗靶点。该计划项目汇集了一群在前列腺癌领域具有广泛和免费的雄激素和AR专业知识的研究人员，并有成就和富有成效的合作记录。每个项目都侧重于促进CRPC中AR活动和功能的不同机制。项目1，去势抵抗前列腺癌中的类固醇代谢(Pi Peter Nelson)，重点是靶向肿瘤内雄激素合成以及对阿比特龙和其他雄激素合成抑制剂的抵抗机制。项目2，CRPC中雄激素受体拮抗剂耐药性的基础(Pi Steven Balk)，重点研究AR拮抗剂的作用机制和耐药性。项目3，通过选择性AR剪接来发展去势抵抗(PJ Stephen Plymate)，重点是替代AR剪接在CRPC中的作用。项目4，CRPC中AR功能的表观遗传重编程(Pi Myles Brown)，重点关注AR转录程序以及它如何随着PCA进展而改变。核心A，行政/临床/生物统计学核心(PI Steven Balk，共同PI Peter Nelson)将协调整个计划，提供生物统计学支持，促进患者材料的获取，并就加强/加速向临床转化的方法提供咨询。核心B，Biospecimen and Animal Models Core(Pi Robert Vessella)，将提供一系列独特的PCA异种移植模型，以及在这些模型中进行单一疗法和联合疗法试验的专业知识和基础设施。Vessella博士还领导了一个非常强大的生物样品收集和处理核心，并将进一步提供适当的临床材料。核心C，类固醇分析核心(Pi Trevor Penning)，将开发和部署所需的最先进的方法来测量人类和小鼠样本中的多种类固醇和代谢物。

DESCRIPTION (provided by applicant): The past several years have seen a paradigm shift in prostate cancer (PCa) therapy; and it is now becoming widely accepted that androgen receptor (AR) remains active and is a therapeutic target in prostate cancers that relapse after surgical or medical castration (castration resistant prostate cancer, CRPC).'This Program Project brings together a group of investigators with extensive and complimentary expertise in androgens and AR in PCa, and with a track record of accomplishments and productive collaborations. Each project focuses on distinct mechanisms that contribute to AR activity and function in CRPC. Project 1, Steroid Metabolism in Castration-Resistant Prostate Cancer (PI Peter Nelson), focuses on targeting intratumoral androgen synthesis and mechanisms of resistance to abiraterone and other inhibitors of androgen synthesis. Project 2, Basis for Androgen Receptor Antagonist Resistance in CRPC (PI Steven Balk), focuses on mechanisms of action and resistance to AR antagonists. Project 3, Development of Castration Resistance by Alternative AR Splicing (PJ Stephen Plymate) focuses on the role of alternative AR splicing in CRPC. Project 4, Epigenetic Reprogramming of AR Function In CRPC (PI Myles Brown) focuses on the AR transcriptional program and how it is altered with PCa progression. Core A, Administrative/Clinical/Biostatistics Core (PI Steven Balk, Co-PI Peter Nelson) will coordinate the overall program, provide biostatistical support, facilitate access to patient materials, and consult on approaches to enhance/accelerate translation to the clinic. Core B, Biospecimen and Animal Models Core (PI Robert Vessella), will provide a unique series of PCa xenograft models in conjunction with the expertise and infrastructure to carry out trials of single and combination therapies in these models. Dr. Vessella also directs a very robust biospecimen collection and processing Core, and will provide further access to appropriate clinical materials. Core C, Steroid Analytical Core (PI Trevor Penning), will develop and deploy needed state-of-the-art methods to measure multiple steroid and metabolites in human and mouse samples.