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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $69,487

## Abstract

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.

## Key facts

- **NIH application ID:** 10599719
- **Project number:** 3R01CA243511-04S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Dineo Khabele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,487
- **Award type:** 3
- **Project period:** 2020-07-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599719

## Citation

> US National Institutes of Health, RePORTER application 10599719, Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer - Diversity Supplement (3R01CA243511-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10599719. Licensed CC0.

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