Role of MED1 in the AR-dependent transcription in advanced prostate cancer

MED1 在晚期前列腺癌 AR 依赖性转录中的作用

• 批准号: 10356845
• 负责人: Irfan Ahmed Asangani
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356845
• 关键词: Address; Androgen Antagonists; Androgen Receptor; Androgens; Antiandrogen Therapy; Applications Grants; Attenuated; Biological Process; CRISPR/Cas technology; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Disease; Disease Progression; Disease Resistance; Drug resistance; Engineering; Enhancers; Event; Foundations; Generations; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Growth; Knock-in; Knowledge; Ligands; Link; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Metastatic Prostate Cancer; Methods; Molecular; Morbidity - disease rate; Mus; Nuclear Receptors; Oncogenic; Oral; Outcome; Patients; Pharmacology; Phase; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Population; Prognostic Marker; Prostate; RNA Polymerase II; Receptor Signaling; Refractory; Refractory Disease; Regulator Genes; Research Design; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Solid; System; Testing; Transcription Coactivator; Transcriptional Regulation; United States; abiraterone; addiction; advanced prostate cancer; anticancer research; castration resistant prostate cancer; cell growth; clinically relevant; enzalutamide; improved; in vivo Model; ineffective therapies; inhibitor; knock-down; mortality; mutant; novel; novel strategies; novel therapeutics; patient derived xenograft model; patient population; pharmacokinetics and pharmacodynamics; potential biomarker; programs; prostate cancer cell; prostate cancer model; small molecule inhibitor; standard of care; success; therapeutic target; therapy resistant; transcription factor; transcriptome; transcriptome sequencing; tumor

Project Summary: Advanced metastatic castration-resistant prostate cancer (CRPC) is an aggressive disease with high mortality rate, primarily resulting from the transcriptional addiction driven by Androgen Receptor (AR) signaling. The evolutionarily conserved multi-subunit Mediator complex plays a central role in the regulation of transcription by virtue of its ability to functionally bridge gene-specific transcription factors with the RNA polymerase II- associated basal transcription machinery. MED1 is a key component of the Mediator complex and is responsible for targeting and anchoring the complex to a broad range of nuclear receptors, including AR. We have identified phosphorylation of MED1 catalyzed by CDK7 transcriptional kinase is required for its interaction with AR and as a rate-limiting step in AR-mediated transcription. The underlying hypothesis of this proposal is that the CDK7 mediated phosphorylation of MED1 is necessary for the formation and stability of MED1-AR complex at the chromatin in both naïve and anti-androgen refractory CRPC which could be targeted by CDK7 specific inhibitors. The goals of this grant application are to investigate the mechanistic basis of MED1-AR interaction further, and evaluate the CDK7 specific inhibitors in reversing the AR-dependent transcriptional addiction in advanced prostate cancer. The three specific aims of the projects are: Specific Aim 1: Investigate the role of p-MED1 in hyper-activation of AR-signaling Specific Aim 2: Investigate the mechanism of increased p-MED1 in enzalutamide refractory PCa. Specific Aim 3: Establish the efficacy of CDK7 inhibitor in clinically relevant naïve and refractory CRPC models in vivo.

项目总结： 晚期转移性去势抵抗前列腺癌(CRPC)是一种高死亡率的侵袭性疾病 率，主要是由雄激素受体(AR)信号驱动的转录成瘾引起的。这个 进化上保守的多亚基介体复合体在转录调控中发挥核心作用 由于它能够在功能上将基因特异的转录因子与RNA聚合酶II- 相关的基础转录机制。MED1是调解人复合体的关键组成部分， 负责靶向并将复合体锚定到包括AR在内的广泛的核受体上。我们 已经发现CDK7转录激酶催化的MED1的磷酸化是其相互作用所必需的 与AR结合，并在AR介导的转录中作为限速步骤。这项提议的基本假设是 CDK7介导的MED1磷酸化是MED1-AR形成和稳定所必需的 天真和抗雄激素难治性CRPC的染色质复合体可被CDK7靶向 特定的抑制剂。这项拨款申请的目的是研究MED-AR的机制基础 进一步相互作用，并评价CDK7特异性抑制剂逆转AR依赖转录的作用 晚期前列腺癌患者成瘾。这些项目的三个具体目标是： 具体目标1：研究p-MED1在AR信号过度激活中的作用 具体目的2：探讨苯扎鲁胺难治性前列腺癌p-MED_1升高的机制。 具体目标3：确定CDK7抑制剂在临床相关的幼稚和难治性CRPC中的疗效 活体模型。