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

前列腺癌中 EZH2 和 PARP 抑制反应和耐药性的分子决定因素

基本信息

批准号：
10628273
负责人：
Himisha Beltran
金额：
$ 47.45万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10628273
关键词：
Acute Adenocarcinoma Androgen Receptor Automobile Driving Biological Biological Markers Biopsy Castration Cells Chromatin Classification Clinical Clinical Data Clinical Research Clinical Trials Combined Modality Therapy Complex DNA Damage DNA Methylation DNA Repair DNA Repair Gene DNA Repair Pathway Dana-Farber Cancer Institute Data Dependence Development Disease Enhancers Epigenetic Process Epithelioid Sarcomas FDA approved Gene Expression Genomics Heterogeneity Histone H3 Homologous Gene Lysine Malignant neoplasm of prostate Measures Mediating Medical Mesothelioma Methylation Modeling Molecular Neuroendocrine Prostate Cancer Neurosecretory Systems Non-Hodgkin&apos s Lymphoma Nonhomologous DNA End Joining PARP inhibition Patients Phase I/II Clinical Trial Phenotype Phosphorylation Play Poly(ADP-ribose) Polymerase Inhibitor Polycomb Process Prostate Prostate Adenocarcinoma Prostate Cancer therapy Receptor Signaling Regulation Repression Repressor Proteins Research Personnel Resistance Role Route Signal Transduction Therapy Clinical Trials Transcription Repressor advanced disease advanced prostate cancer biomarker identification castration resistant prostate cancer cofactor derepression drug sensitivity epigenomics gene repair gene repression histone methylation homologous recombination inhibitor inhibitor therapy insight member men neoplastic cell neuroendocrine phenotype novel novel therapeutic intervention overexpression patient derived xenograft model patient subsets pharmacodynamic biomarker preclinical study programs prostate cancer model prostate cancer progression response response biomarker safety assessment synergism synovial sarcoma targeted treatment therapy duration therapy resistant tumor tumor growth

项目摘要

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.

项目概要 - 项目 2 去势抵抗性前列腺癌（CRPC）是一种致命的疾病。表观遗传失调，包括 zeste 同源物 2 (EZH2) 增强子的过度表达会导致治疗耐药，而 EZH2 抑制剂是在临床试验中。除了作为 PRC2 复合体成员的转录抑制因子的典型作用之外，我们先前确定了 EZH2 在激活 AR 信号传导以及驱动谱系中的非典型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物的活动可能受到限制并应采取组合战略。我们最近发现了 EZH2 之间的一种新的相互作用 DNA 修复过程以及前列腺癌中 EZH2 和 PARP 抑制之间的协同作用。我们假设 EZH2 通过规范和非规范驱动下游分子程序机制，并且这些下游影响是依赖于环境的。 EZH2 和 EZH2 的联合治疗因此，PARP 抑制将根据潜在的基因组对 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EZH2调节DNA修复的机制并定义 DNA 修复途径如何影响 EZH2 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，EZH2 和 PARP 抑制对 CRPC 异质谱的影响和临床研究。我们将开展一项由研究者发起的 EZH2i（tazemetostat）+ 的首次现场临床试验 PARPi (talazoparib) 具有广泛的翻译相关性。该项目的结果将为男性 CRPC 的新治疗策略。