Chemical Epigenomic Strategies to Overcome Metastatic Castration Resistant Prostate Cancer

摘要 核受体是赋予细胞身份的类固醇依赖性转录因子。他们指导 发育，并维持成人组织的稳态，如睾酮反应性雄激素 控制雄性特异性组织的受体。异常AR驱动的基因表达程序引起 前列腺癌当雄激素剥夺治疗（ADT）后出现抵抗时，疾病进展到 更致命的转移性去势抵抗性前列腺癌（mCRPC）， 通过过度表达AR治疗。新的证据表明，许多其他转录因子和表观遗传 辅激活蛋白可能与AR一起产生疾病特异性增强子，以驱动肿瘤，特别是在 治疗复发的mCRPC。作为一个训练有素的合成化学家，分子生物学家和计算 作为一名生物学家，我将在新的临床相关类器官模型中绘制mCRPC中工作的表观遗传机制。我 我将展示如何使用我发现的具有新作用机制的小分子来阻止AR轴， AR经历化学诱导的功能转换，导致AR抑制肿瘤驱动基因 它通常会激活。此外，我的目标是揭示共同依赖的表观遗传蛋白，这些蛋白驱动晚期阶段， 疾病，并使用新的分子干扰CBP/p300（组蛋白乙酰转移酶，建立积极的增强子） 作为一种策略，选择性地阻止基因驱动疾病复发。在这项工作结束时，我们应该 具有在反向激动剂的影响下的AR的第一机理理解，提供功能性的 表观遗传图谱的调节成瘾在先进的PCa，并探讨了治疗潜力的前景 新的AR疗法

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.