Chemical Epigenomic Strategies to Overcome Metastatic Castration Resistant Prostate Cancer

克服转移性去势抵抗性前列腺癌的化学表观基因组策略

基本信息

批准号：
10415858
负责人：
Berkley E Gryder
金额：
$ 17.51万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-02 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415858
关键词：
AR gene Acetylation Adult Agonist Androgen Antagonists Androgen Receptor Animal Model Automobile Driving Biochemical Biological CRISPR screen Cell Line Cells ChIP-seq Chemicals Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Dependence Deposition Development Disease EP300 gene Enhancers Enzymes Epigenetic Process Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Heart Histones Homeostasis Learning Lysine Malignant Neoplasms Malignant neoplasm of prostate Maps Modeling Molecular Mutagenesis Neuroendocrine Prostate Cancer Neurosecretory Systems Nuclear Receptors Oncogenic Organoids Output Patients Pharmaceutical Preparations Process Proteins Recurrence Recurrent disease Regulator Genes Relapse Resistance Route Sampling Specific qualifier value Steroid Receptors Testing Testosterone Therapeutic Tissues Training Transferase Work addiction advanced disease advanced prostate cancer androgen deprivation therapy androgen sensitive castration resistant prostate cancer cell type clinically relevant deprivation enzalutamide epigenomics genetic corepressor genome-wide lens male novel overexpression patient derived xenograft model predict responsiveness programs prostate cancer cell line recruit resistance mechanism small molecule targeted treatment therapeutic evaluation therapy resistant transcription factor transcriptome sequencing tumor

项目摘要

ABSTRACT Nuclear receptors are steroid-dependent transcription factors that confer cell identity. They guide development, and maintain homeostasis in adult tissue, such as the testosterone responsive Androgen Receptor which governs male-specific tissues. Aberrant AR-driven gene expression programs give rise to prostate cancer. When resistance arises after androgen-deprivation therapy (ADT) the disease advances to the much more lethal metastatic castration-resistant prostate cancer (mCRPC), becoming resistant to these therapies by overexpressing AR. New evidence suggests that many other transcription factors and epigenetic co-activator proteins may create disease-specific enhancers with the AR to drive tumors, especially in treatment-relapsed mCRPC. As a well-trained synthetic chemist, molecular biologist and computational biologist, I will map the epigenetic mechanisms at work in mCRPC, in new clinically relevant organoid models. I will show how to stop the AR-axis using small molecules I discovered with novel mechanisms of action, where the AR undergoes a chemically induced functional switch, causing the AR to suppress the tumor-driving genes it normally activates. Additionally, I aim to uncover co-dependency epigenetic proteins which drive late stage disease, and use new molecules perturbing CBP/p300 (histone acetyl transferases that build active enhancers) as a strategy to selectively halt the genes driving disease relapse. At the conclusion of this work, we should have the first mechanistic understanding the AR under the influence of an inverse agonist, provide functional epigenetic map of regulatory addictions in advanced PCa, and have explored therapeutic potential of promising new AR therapeutics.

抽象的核受体是类固醇依赖性的转录因子，赋予细胞身份。他们指导开发并维持成人组织中的稳态，例如睾丸激素反应雄激素控制男性特异性组织的受体。异常AR驱动的基因表达程序产生前列腺癌。当雄激素剥夺治疗（ADT）之后产生抗药性时，疾病会发展为更具致命的转移性cast割前列腺癌（MCRPC），对这些癌症具有抵抗力通过过表达AR的疗法。新证据表明许多其他转录因子和表观遗传因素共激活蛋白可能会与AR产生特异性增强剂以驱动肿瘤，尤其是在与治疗相关的MCRPC。作为训练有素的合成化学家，分子生物学家和计算生物学家，我将在新的临床相关类器官模型中绘制MCRPC工作中的表观遗传机制。我将展示如何使用我发现使用新颖的作用机理发现的小分子来停止AR轴，其中 AR经历了化学诱导的功能开关，导致AR抑制肿瘤驱动基因它通常激活。此外，我的目标是发现共同依赖性的表观遗传蛋白，这些蛋白可以驱动后期疾病，并使用新的分子扰动CBP/P300（组蛋白乙酰转移酶，产生活跃增强剂）作为选择性停止驱动疾病复发的基因的策略。在这项工作结束时，我们应该在反向激动剂的影响下具有第一个机械理解AR，提供功能高级PCA中调节成瘾的表观遗传图，并探索了有希望的治疗潜力新的AR治疗学。