Androgen Receptor Action in Castration Resistant Prostate Cancer

雄激素受体在去势抵抗性前列腺癌中的作用

基本信息

批准号：
8475909
负责人：
Steven P. Balk
金额：
$ 218.35万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-24 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475909
关键词：
Achievement Androgen Antagonists Androgen Receptor Androgens Animal Model Automobile Driving Basic Science Benchmarking Biostatistics Core CYP17A1 gene Cancer Relapse Castration Clinic Clinical Clinical Research Clinical Trials Collaborations Collection Combined Modality Therapy Consult Development EZH2 gene Epigenetic Process Foundations Goals Human Institution Malignant neoplasm of prostate Measures Mediating Medical Castration Methodology Methods Modeling Molecular Mus Mutation New Agents Patients Pre-Clinical Model Pregnanes Principal Investigator Process Prostate Cancer therapy Proteins RNA Splicing Records Relapse Research Infrastructure Research Personnel Resistance Role Sampling Series Steroids Therapeutic Translational Research Translations Variant Work Xenograft Model abiraterone base castration resistant prostate cancer clinical material clinically relevant gene repression inhibitor/antagonist novel novel therapeutic intervention novel therapeutics programs receptor function resistance mechanism response steroid metabolism success therapeutic target tumor progression

项目摘要

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.

描述（由申请人提供）：过去几年，前列腺癌（PCa）治疗发生了范式转变；现在人们普遍认为雄激素受体 (AR) 仍然活跃，并且是手术或药物去势后复发的前列腺癌（去势抵抗性前列腺癌，CRPC）的治疗靶点。在雄激素和前列腺癌 AR 方面拥有广泛且互补的专业知识，并拥有良好的成就和富有成效的合作记录。每个项目都侧重于有助于 CRPC 中 AR 活动和功能的不同机制。项目 1，去势抵抗性前列腺癌中的类固醇代谢（PI Peter Nelson），重点关注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耐药机制。项目 2，CRPC 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，通过替代性 AR 剪接开发去势抵抗力 (PJ Stephen Plymate) 重点研究替代性 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）重点研究 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/生物统计核心（PI Steven Balk，Co-PI Peter Nelson）将协调整个计划，提供生物统计支持，方便获取患者材料，并就增强/加速临床转化的方法进行咨询。核心 B、生物样本和动物模型核心（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和组合疗法试验的专业知识和基础设施。 Vessella 博士还负责指导一个非常强大的生物样本收集和处理核心，并将提供对适当临床材料的进一步访问。 Core 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。