Project 1: Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell Proliferation and Survival

项目 1：确定和利用 AR 介导的细胞增殖和存活抑制机制

• 批准号: 10576936
• 负责人: PETER S NELSON
• 金额: $ 39.59万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576936
• 关键词: Androgen Receptor; Androgens; Antitumor Response; Apoptotic; Automobile Driving; Biological Models; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell Survival; Clinical; Collaborations; Complex; Controlled Clinical Trials; DNA; Data; Development; Disease; Disease remission; Drug Combinations; Environment; Epigenetic Process; Generations; Genes; Genetic Transcription; Genomics; Growth; Hormones; Human; In Vitro; Ligands; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Modification; Molecular; Molecular Abnormality; Mutation; Nature; Neoplasm Metastasis; Oncogenic; Organoids; Pathway interactions; Patients; Phase; Physiological; Pre-Clinical Model; Process; Proliferating; RNA Splicing; Receptor Signaling; Relapse; Reporting; Repression; Reproducibility; Research Design; Resistance; Series; Signal Induction; Signal Pathway; Signal Transduction; Site; TMPRSS2 gene; Testing; Testosterone; Therapeutic; Tumor Suppressor Proteins; Tumor-Associated Process; Variant; Work; androgen deprivation therapy; androgen sensitive; antitumor effect; biomarker identification; cancer survival; carcinogenesis; castration resistant prostate cancer; clinical practice; epigenomics; genetic corepressor; genome-wide; genome-wide analysis; men; neoplastic cell; novel; overexpression; patient derived xenograft model; pre-clinical; preclinical study; predicting response; predictive marker; programs; prostate cancer progression; resistance mechanism; response; selective androgen receptor modulator; senescence; synergism; treatment strategy; tumor; tumor growth

Since the inception of clinical efforts in prostate cancer (PCa) to suppress androgen receptor (AR) signaling by reducing AR ligands (androgen deprivation therapy, ADT), it was recognized that the administration of testosterone (T) to men who have relapsed after ADT (castration-resistant prostate cancer, CRPC) could result in substantial clinical responses. However, these reports were largely anecdotal and remissions were highly variable. In contrast, abundant data from preclinical models have reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T concentrations proliferation is induced, but at higher, supraphysiological androgen (SPA) concentrations, proliferation is suppressed and in some instances apoptotic programs are engaged. Though often considered to be an in vitro phenomenon of little clinical importance, recent rigorously controlled clinical trials of SPA produced substantial clinical responses in subsets of men with CRPC. Collectively, these findings support studies designed to determine the molecular mechanism(s) driving these responses. Based on these preclinical and clinical findings to date, we hypothesize that the genomic and epigenomic adaptive processes that contribute to CRPC progression also sensitize tumor cells to the differentiation, quiescence and apoptotic programs regulated by the AR under conditions of SPA. We will test this hypothesis through three linked aims: AIM 1. Determine the primary mechanism(s) by which SPA represses CRPC. AIM 2. Define the AR cistrome in prostate cancers reprogrammed by SPA and identify cooperating genes and pathways that are essential or suppressive of SPA effects. AIM 3. Identify drug combinations that synergize with SPA to repress tumor growth and optimize the effects of AR agonism based on a mechanistic understanding of SPA-mediated growth arrest.

自从前列腺癌(PCa)抑制雄激素受体(AR)的临床研究开始 通过减少AR配体的信号传递(雄激素剥夺疗法，ADT)，人们认识到 对抗去势前列腺癌(ADT)后复发的男性服用睾酮(T) 癌症，CRPC)可能会导致实质性的临床反应。然而，这些报道主要是 轶事和缓解是高度可变的。相比之下，来自临床前模型的大量数据 可重复性地显示激素敏感型癌症的双相反应，因此在生理T 浓度会诱导增殖，但在较高的超生理学雄激素(SPA)浓度下， 增殖受到抑制，在某些情况下还参与了凋亡计划。尽管经常 被认为是一种临床意义不大的体外现象，最近严格控制临床 SPA的试验在CRPC男性亚群中产生了实质性的临床反应。总而言之，这些 研究结果支持旨在确定驱动这些反应的分子机制(S)的研究。 基于到目前为止的这些临床前和临床研究结果，我们假设基因组和 有助于CRPC进展的表观基因组适应过程也使肿瘤细胞对 在SPA条件下，AR调控的分化、静止和凋亡程序。我们会 通过三个相互关联的目标来检验这一假设：目标1.确定主要机制(S)，通过 SPA抑制CRPC。目的2.确定SPA和SPA重编程前列腺癌中的AR周期 确定SPA效应的基本或抑制的协同作用基因和途径。目标3. 确定与SPA协同抑制肿瘤生长并优化其作用的药物组合 AR激动症建立在对SPA介导的生长停滞的机械理解基础上。