# Project 2: Combination PARPi-BETi to Overcome PARPi Resistance

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $440,092

## Abstract

ABSTRACT – PROJECT 2
PARP inhibitors have emerged as an established standard of care option in epithelial ovarian cancer (OvCa).
Approximately half of OvCa patients harbor inactivating genetic alterations in the homologous recombination
(HR) pathway, which results in synthetic lethality with PARP inhibition (PARPi). PARPi have promising activity
in HR-deficient OvCa. Even though less effective compared to HR-deficient OvCa, PARPis have also been
shown to be active in HR-proficient OvCa. Unfortunately, the activity of PARPi is limited by the emergence of
PARPi resistance. Therefore, there is an urgent need to identify potential strategies to reverse PARPi resistance
in OvCa. Our preliminary studies suggest that inhibition of BRD4 activity by bromodomain extraterminal inhibitors
(BETi) is an attractive approach to reverse PARPi resistance. Notably, the BRD4 genomic locus 19p13.12 is
often amplified in high-grade serous OvCa (~20%). Indeed, BRD4 amplification/overexpression correlates with
a poor prognosis in these patients.
We and others have shown that BETis play a major role in suppressing the HR pathway and impairing the G2/M
checkpoint, which reverses resistance to PARPi caused by restoration of the HR pathway. Therefore, our
central hypothesis is that targeting BRD4 activity using clinically applicable BET inhibitor is sufficient
to overcome resistance to PARPi developed in recurrent OvCa. We also hypothesize that targeting BRD4
will sensitize tumor to PARPi by simultaneously downregulating HR activity, specifically BRCA1, RAD51 and
TOPBP1 expression, and impairing the G2/M phase of the cell cycle by suppressing WEE1 activity, leading to
DNA damage accumulation and mitotic catastrophe. Accordingly, the objective of the present study is to
evaluate the safety and efficacy of a combination of PARPi and BETi in recurrent PARPi-resistant
platinum-sensitive OvCa. We also plan to assess the impact of PARPi-BETi combination on functional HR
activity and percent reduction compared to baseline and correlate with objective response to therapy. Further,
we plan to investigate the mechanistic basis of these findings in patient-derived models obtained from the
patients enrolled in the trial. To achieve that, we propose the following specific aims (SA): SA1. To determine
the safety and efficacy of PARPi combined with BETi in patients with recurrent PARPi-resistant OvCa in a phase
Ib clinical trial. SA2. To investigate the impact of the combined regimen on modulating HR and DNA damage
response (DDR) pathways as well as G2-M cell cycle checkpoint using tissue and circulating tumor DNA samples
both at baseline, on treatment and at time of progression. SA3: To investigate the mechanisms of response and
resistance to the combination regimen in preclinical models. The potential impact is significant as there is an
urgent need to overcome resistance to PARPi in OvCa. This project investigates a novel new therapeutic
direction combining PARPi with epigenetic therap...

## Key facts

- **NIH application ID:** 10925282
- **Project number:** 5P50CA272218-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Haider Mahdi
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,092
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925282

## Citation

> US National Institutes of Health, RePORTER application 10925282, Project 2: Combination PARPi-BETi to Overcome PARPi Resistance (5P50CA272218-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10925282. Licensed CC0.

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