# Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $105,398

## Abstract

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 ...

## Key facts

- **NIH application ID:** 11075402
- **Project number:** 3R01CA243511-06S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Dineo Khabele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $105,398
- **Award type:** 3
- **Project period:** 2020-07-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11075402

## Citation

> US National Institutes of Health, RePORTER application 11075402, Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer (3R01CA243511-06S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11075402. Licensed CC0.

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