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

项目摘要--项目2 抗去势前列腺癌(CRPC)是一种致命性疾病。表观遗传失调，包括 Zust Homolog 2增强子(EZH2)的过表达会导致治疗耐药性，而EZH2抑制剂是 在临床试验中。除了作为PRC2复合体的成员作为转录抑制因子的典型角色外，我们 以前发现了EZH2在激活AR信号和驱动谱系方面的非典型作用 可塑性与神经内分泌前列腺癌。目前的数据表明，单一因素的活动可能是有限的 而这种结合战略应该得到推行。我们最近发现了一种新的EZH2之间的相互作用 以及DNA修复过程以及EZH2和PARP抑制在前列腺癌中的协同作用。我们 假设EZH2通过正则和非正则驱动下游分子程序 机制，并且这些下游影响取决于上下文。EZH2和EZH2联合治疗 因此，基于潜在的基因组，PARP抑制将对CRPC产生不同的生物学影响， 表观基因组学和表型背景。我们将阐明EZH2调节DNA修复的机制 并确定DNA修复途径如何影响EZH2的药物敏感性。我们将对生物和临床进行评估。 EZH2和PARP抑制通过广泛的临床前对CRPC异质性谱的影响 和临床研究。我们将进行一项由研究人员发起的EZH2(TazemTostat)plus的现场首个临床试验 PARPI(他唑巴利)具有广泛的翻译相关性。该项目的结果将为 男性慢性前列腺癌的新治疗策略。

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.