Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer - Diversity Supplement

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the deadliest gynecologic cancer and is the fifth leading cause of cancer death among women in the United States. Poly (ADP-ribose) polymerase inhibitors (PARPi) have long been used in the treatment BRCA mutant homologous-recombination (HR) deficient ovarian cancers. A substantial subset of high-grade serous ovarian cancers (HGSC) are HR proficient and are resistant to PARPi; thus resulting in poor prognostic ovarian cancers (CCNE1 amplification/gain). Preclinical models of HR proficient ovarian cancer have shown that combining PARPi with epigenetic drugs, resulted in “BRCA mutant-like” contextual- synthetic lethal phenotype; which was characterized by repressed HR gene expression and function. The PI has demonstrated the success of combining histone deacetylase inhibitors (HDACi), bromodomain extra- terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi) with PARPi in preclinical models of HR proficiency. However, gaps still remain in the optimal combination therapy. In our parent grant, we hypothesized 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. Unlike traditional 2D primary cultures, organoid cultures provide a unique in vitro model which better recapitulates tissue morphology and cellular heterogeneity. We hypothesize that patient- derived organoids are better representatives of the tumor microenvironment for screening of first-line and novel drug combinations to treat ovarian cancer. We will pursue two Specific Aims: 1) Evaluate patient- derived ovarian organoids for olaparib and platinum sensitivity, followed by the screening of PARPi and epigenetic drugs combination therapy and 2) Identify biomarkers to assess the status of tumor response to olaparib and entinostat combination therapy, using organoids developed from available patient biopsies and the PI’s clinical trial. In addition data from the funded R01, this supplement will lead to novel combination therapeutic strategies and the identification of surrogate biomarkers to assess treatment efficiency.