# Overcoming platinum resistance in ovarian cancer through BET inhibition.

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2021 · $256,091

## Abstract

PROJECT 3: PROJECT SUMMARY
The overall goal of this proposal is to determine whether the bromodoman and extra-terminal (BET) protein
BRD4 is a promising therapeutic target for delaying and/or overcoming resistance to platinum-based ovarian
cancer standard of care. Chemoresistance is a major cause of the high mortality of ovarian cancer and in
particular in the most common high-grade serous carcinoma (HGSC). Substantial evidence suggests that
cells with cancer stem-like cells (CSC) characteristics contribute to chemotherapy resistance. Putative
ovarian cancer CSCs are typically characterized by increased aldehyde dehydrogenase (ALDH) activity. This
is a hypothesis-driven translational study, and the findings will be pivotal for evaluating whether BET inhibitors
in combination with platinum represents an effective approach for overcoming platinum resistance by
suppressing ALDH activity in ovarian cancer CSCs. We will collaborate with Incyte, Inc. to use their BET
inhibitor INCB57643 that is proven safe in patients. Thus, the BET inhibitor is readily available for immediate
translation in ovarian cancer. The proposed studies are based on our recent findings established that inhibition
of BRD4 activity by BET inhibitors is sufficient to eradicate ALDH positive CSCs. Our central hypothesis is
that platinum resistance can be overcome through eliminating ALDH positive cancer stem-like cells by
targeting BRD4 using clinical applicable small molecule BET inhibitor INCB57643. Three Specific Aims are
proposed: Aim 1 will explore the combination of BET inhibitor INCB57643 and carboplatin in patients with
HGSOC in a Phase 1 clinical trial; Aim 2 will investigate the combinational therapeutic strategy of targeting
BRD4 using BET inhibitor INCB57643 and carboplatin in HGSC cell lines and patient-derived xenografts; and
Aim 3 will identify companion biomarkers that correlate with response to BET inhibitor INCB57643 and
carboplatin combination in HGSOCs. The proposed studies are highly innovative because they challenge
current research/clinical paradigms, contribute to new concepts for epigenetic therapeutics by combining BET
inhibitors and platinum, and utilize innovative methods to explore new intervention strategies for
chemotherapy resistance in ovarian cancer. The proposed studies are of high impact because these studies
will develop therapeutic strategies with a durable therapeutic outcome by overcoming platinum resistance
through eradicating cancer stem-like cells, a major challenge in the clinical management of ovarian cancer.

## Key facts

- **NIH application ID:** 10222606
- **Project number:** 5P50CA228991-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Rugang Zhang
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $256,091
- **Award type:** 5
- **Project period:** 2018-09-18 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222606

## Citation

> US National Institutes of Health, RePORTER application 10222606, Overcoming platinum resistance in ovarian cancer through BET inhibition. (5P50CA228991-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10222606. Licensed CC0.

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