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: 10626720
• 负责人: Irfan Ahmed Asangani
• 金额: $ 36.43万
• 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/10626720
• 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; Metastatic Prostate Cancer; Methods; Molecular; Morbidity - disease rate; Mus; Nuclear Receptors; Oncogenic; Oral; Outcome; Patients; 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; pharmacologic; 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.

项目摘要： 晚期转移性去势抵抗性前列腺癌（CRPC）是一种侵袭性疾病，死亡率高 速率，主要由雄激素受体（AR）信号传导驱动的转录成瘾引起。的 进化上保守的多亚基介导复合物在转录调控中起着核心作用， 由于其能够在功能上桥接基因特异性转录因子与RNA聚合酶II- 相关的基础转录机器。MED 1是Mediator复合体的关键组成部分， 负责将复合物靶向和锚定到广泛的核受体，包括AR。我们 我已经确定了由CDK 7转录激酶催化的MED 1磷酸化是其相互作用所必需的 在AR介导的转录过程中作为限速步骤。这一提议的基本假设是 CDK 7介导的MED 1磷酸化对MED 1-AR的形成和稳定是必需的， CDK 7可以靶向的初治和抗雄激素难治性CRPC染色质上的复合物 特异性抑制剂本基金申请的目的是研究MED 1-AR的机制基础 进一步相互作用，并评估CDK 7特异性抑制剂在逆转AR依赖性转录中的作用。 晚期前列腺癌的治疗这些项目的三个具体目标是： 具体目的1：研究p-MED 1在AR信号传导过度激活中的作用 具体目标2：研究恩杂鲁胺难治性PCa中p-MED 1增加的机制。 具体目标3：确定CDK 7抑制剂在临床相关初治和难治性CRPC中的疗效 体内模型。