Molecular Determinants of Response and Resistance to EZH2 and PARP inhibition in Prostate Cancer

项目概要-项目2 去势抵抗性前列腺癌（CRPC）是一种致死性疾病。表观遗传失调，包括 zeste增强子同源物2（EZH 2）的过表达驱动治疗抗性，并且EZH 2抑制剂是 在临床试验阶段除了作为PRC 2复合体成员作为转录抑制因子的典型作用外，我们还发现， 先前确定了EZH 2在激活AR信号传导以及驱动谱系中的非经典作用， 可塑性和神经内分泌前列腺癌目前的数据表明，单一药剂的活性可能有限 应采取组合策略。我们最近发现了EZH 2与 和DNA修复过程以及前列腺癌中EZH 2和PARP抑制之间的协同作用。我们 假设EZH 2通过规范和非规范驱动下游分子程序， 机制，这些下游效应是依赖于上下文的。与EZH 2和 因此，基于基础基因组，PARP抑制将对CRPC产生不同的生物学影响， 表观基因组和表型背景。我们将阐明EZH 2调节DNA修复的机制 并确定DNA修复途径如何影响EZH 2药物敏感性。我们将评估生物学和临床 通过广泛的临床前研究，EZH 2和PARP抑制对CRPC异质谱的影响 和临床研究。我们将进行EZH 2 i（tazemetostat）+的首次现场，药物启动的临床试验 PARPi（talazoparib）具有广泛的翻译相关性。该项目的结果将为 CRPC男性患者的新治疗策略。

PROJECT SUMMARY- PROJECT 2 Castration resistant prostate cancer (CRPC) is a lethal disease. Epigenetic dysregulation, including overexpression of the enhancer of zeste homolog 2 (EZH2) drives treatment resistance, and EZH2 inhibitors are in clinical trials. Beyond its canonical role as a member of the PRC2 complex as a transcriptional repressor, we previously identified a non-canonical role of EZH2 in activating AR signaling, as well as in driving lineage plasticity and neuroendocrine prostate cancer. Current data suggests that single agent activity may be limited and that combination strategies should be pursued. We recently discovered a novel interaction between EZH2 and DNA repair processes and a synergy between EZH2 and PARP inhibition in prostate cancer. We hypothesize that EZH2 drives downstream molecular programs through canonical and non-canonical mechanisms, and that these downstream effects are context dependent. Combination therapy with EZH2 and PARP inhibition will therefore have differential biologic impact in CRPC based on the underlying genomic, epigenomic, and phenotypic context. We will elucidate the mechanisms by which EZH2 regulates DNA repair and define how DNA repair pathways impact EZH2 drug sensitivity. We will evaluate the biologic and clinical impact of EZH2 and PARP inhibition across the heterogeneous spectrum of CRPC through extensive preclinical and clinical studies. We will conduct a first-in-field, investigator-initiated clinical trial of EZH2i (tazemetostat) plus PARPi (talazoparib) with extensive translational correlates. Results from this project will provide the basis for a new therapeutic strategy for men with CRPC.