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.

项目摘要 - 项目2 耐castation的前列腺癌（CRPC）是一种致命的疾病。表观遗传失调，包括 Zeste同源物2（EZH2）增强子的过表达驱动治疗性，EZH2抑制剂是在临床试验中。除了其作为PRC2复合物成员作为转录阻遏物的成员的规范作用之外，我们还以前确定了EZH2在激活AR信号传导以及驱动谱系中的非规范作用可塑性和神经内分泌前列腺癌。当前数据表明单位代理活动可能受到限制并且应该采取这种组合策略。我们最近发现了EZH2之间的一种新颖的相互作用前列腺癌中EZH2和PARP抑制作用之间的DNA修复过程以及协同作用。我们假设EZH2通过规范和非规范驱动下游分子程序机制，并且这些下游效应取决于上下文。与EZH2和因此，PARP抑制作用将基于潜在的基因组，对CRPC产生差异性生物学影响表观基因组和表型环境。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 EZH2和PARP抑制在CRPC异质范围内通过广泛的临床前的影响和临床研究。我们将进行EZH2I（TazeMetostat）Plus的第一场领域，研究人员发起的临床试验 Parpi（Talazoparib）具有广泛的翻译相关性。该项目的结果将为 CRPC男性的新治疗策略。