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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：晚期转移性去势抵抗性前列腺癌（CRPC）是一种具有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。进化上保守的多亚基介体复合体在转录调节中发挥核心作用凭借其将基因特异性转录因子与 RNA 聚合酶 II 功能桥接的能力，相关的基础转录机制是介导复合体的关键组成部分。负责将复合物靶向并锚定到广泛的核受体上，包括 AR We。已确定 CDK7 转录激酶催化的 MED1 磷酸化是其相互作用所必需的与 AR 并作为 AR 介导的转录的限速步骤该提议的基本假设是 CDK7 介导的 MED1 磷酸化对于 MED1-AR 的形成和稳定性是必需的天然 CRPC 和抗雄激素难治性 CRPC 中染色质上的复合物可以被 CDK7 靶向本次拨款申请的目标是研究 MED1-AR 的机制基础。进一步相互作用，并评估 CDK7 特异性抑制剂逆转 AR 依赖性转录的作用该项目的三个具体目标是：具体目标 1：研究 p-MED1 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-MED1 增加的机制。具体目标 3：确定 CDK7 抑制剂在临床相关的初治和难治性 CRPC 中的疗效体内模型。