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.

项目摘要：晚期转移性castration-耐药前列腺癌（CRPC）是一种侵略性疾病，死亡率很高速率，由雄激素受体（AR）信号传导转录成瘾驱动而产生的主要速率。这进化配置的多重亚基调解人复合物在调节转录中起着核心作用它的优点是其功能桥接基因特异性转录因子的能力相关的基本转录机械。 Med1是调解员综合体的关键组成部分，是负责将复合物靶向和固定到包括AR在内的各种核接收器。我们已经确定了由CDK7转录激酶催化的MED1的磷酸化，其相互作用需要用AR并作为AR介导的转录的速率限制步骤。该提议的基本假设是 CDK7介导的Med1的磷酸化对于Med1-AR的形成和稳定性是必需的染色质和抗雄激素难治性CRPC的染色质络合物，CDK7可以靶向特定抑制剂。该赠款申请的目标是调查Med1-ar的机械基础进一步相互作用，并评估CDK7特异性抑制剂在逆转AR依赖性转录时晚期前列腺癌成瘾。项目的三个具体目标是：特定目标1：研究p-Med1在AR信号过度激活中的作用具体目标2：研究恩扎拉胺难治性PCA中P-MED1增加的机理。特定目标3：确定CDK7抑制剂在临床相关的幼稚和难治性CRPC中的效率体内模型。