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

• 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
• 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

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）：过去几年中，前列腺癌（PCa）治疗发生了范式转变;目前已被广泛接受的是，雄激素受体（AR）保持活性，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。“这个计划项目汇集了一组在雄激素和AR在PCa方面具有广泛和互补专业知识的研究人员，并具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活性和功能的不同机制。项目1，去势抵抗性前列腺癌中的类固醇代谢（PI Peter纳尔逊），重点关注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耐药机制。项目2，CRPC中雄激素受体拮抗剂耐药性的基础（PI Steven Balk），重点关注AR拮抗剂的作用机制和耐药性。项目3，通过替代AR剪接产生去势抵抗（PJ Stephen Plymate），重点关注替代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）专注于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，Co-PI Peter纳尔逊）将协调整个项目，提供生物统计学支持，促进患者材料的访问，并就增强/加速向诊所翻译的方法提供咨询。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，并结合专业知识和基础设施，在这些模型中进行单一和联合治疗试验。Vessella博士还指导一个非常强大的生物标本收集和处理核心，并将提供进一步访问适当的临床材料。核心C，类固醇分析核心（PI特雷弗潘宁），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。