权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

同源重组卵巢癌的表观遗传药物治疗方案

基本信息

批准号：
10117210
负责人：
Dineo Khabele
金额：
$ 44.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117210
关键词：
Address Aftercare Back Biological Assay Biological Markers Blood specimen Bromodomain CCNE1 gene Cancer Model Cell Line ChIP-seq Chemicals Clinic Clinical Clinical Trials Complement DNA Methyltransferase Inhibitor Data Drug Combinations Epigenetic Process Future Gene Expression Genes Genetic Transcription Histone Deacetylase Inhibitor In Vitro Knowledge Malignant neoplasm of ovary Measures Methods Molecular Patients Pharmaceutical Preparations Phase I/II Clinical Trial Phase I/II Trial Phenotype Platinum Poly(ADP-ribose) Polymerases Positioning Attribute Pre-Clinical Model Publishing Regimen Repression Resistance Surrogate Markers Testing Therapeutic Toxic effect Translational Research Validation antitumor effect cancer cell cell type chemotherapy clinical development clinically relevant companion diagnostics design effective therapy epigenetic drug epigenetic therapy gene function genome-wide homologous recombination in vivo inhibitor/antagonist innovation insight mutant patient derived xenograft model pre-clinical preclinical development prognostic response response biomarker transcriptome sequencing translational approach tumor

项目摘要

Poly ADP ribose polymerase inhibitors (PARPi) have shown extraordinary clinical benefits in the treatment of BRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem is chemotherapy drugs, including PARPi, are far less effective in BRCA wild-type HR proficient, poor prognostic ovarian cancer (e.g. CCNE1 amplification/gain). Combining PARPi with other drugs is an emerging strategy to overcome this problem. The PI has shown epigenetic drugs, histone deacetylase inhibitors (HDACi), bromodomain extra-terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi), enhance PARPi efficacy in preclinical models of HR proficient ovarian cancer. Epigenetic drugs primarily activate or repress gene transcription in a cell type- and context-dependent manner. In the context of CCNE1 amplified/gain HR proficient ovarian cancer, the PI has demonstrated chemically diverse epigenetic drugs induce a “BRCA mutant-like” contextual synthetic lethal phenotype, characterized by repressed HR gene expression and function. The overall objective of this proposal is to determine if the extraordinary benefits of PARPi therapy can be extended through rational PARPi-epigenetic drug combinations for a new indication in BRCA wild-type HR proficient, poor prognostic ovarian cancer. Even with extensive published and preliminary results from the PI's group and others, gaps in knowledge remain regarding optimal PARPi-epigenetic regimens for clinical use, appropriate biomarkers of response, and precise underlying mechanisms of action. To address these gaps, we will apply a translational research approach that takes full advantage of our collective expertise including: unique primary cell lines and patient-derived xenograft (PDX) preclinical models, clinical patient biosamples associated with an approved phase 1/2 trial, and state-of-the-art genome-wide strategies. As a result, we are perfectly positioned to test the central hypothesis that epigenetic drugs enhance PARPi efficacy in BRCA wild-type HR proficient ovarian cancer by inducing a BRCA mutant-like phenotype through repression of common HR transcriptional targets and contextual synthetic lethality. The Specific Aims are designed to determine the therapeutic potential of new PARPi-epigenetic drug regimens in preclinical models of ovarian cancer, to investigate HR deficient status as a surrogate biomarker of a new PARPi-epigenetic drug regimen in clinical development, and to elucidate mechanisms of response to PARPi-epigenetic drug regimens in HR proficient ovarian cancer cells using genome-wide strategies. This innovative translational approach has high potential for advancing new preclinical PARPi-epigenetic drug regimens to the clinic, along with new biomarkers as companion diagnostics, and new mechanistic insights for both PARPi and epigenetic drugs. As a result, the proposed studies will have broad implications beyond ovarian cancer. Because a critical clinical problem is the lack of effective treatment options for BRCA wild-type HR proficient tumors, establishing benefits of PARPi-epigenetic therapy for this typically poor prognostic ovarian cancer has the potential for high impact.

聚ADP核糖聚合酶抑制剂（PARPi）已显示出非凡的临床效益治疗