# Metabolic basis of ARID1A-mutated ovarian cancer

> **NIH NIH R01** · WISTAR INSTITUTE · 2022 · $184,954

## Abstract

Project Summary
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated
epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of
ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an
unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is
generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in
advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this
proposal is to develop a novel therapeutic strategy for ARID1A-mutated ovarian cancers by combining a
clinically applicable metabolic glutaminase inhibitor with an immune checkpoint blockade. We show that the
ARID1A inactivation creates a dependence on the glutamine metabolism. We also show that ARID1A
inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to
investigate the mechanisms underlying the dependence on the glutamine metabolism created by ARID1A
inactivation and to investigate a combination therapeutic strategy for ARID1A-mutated ovarian cancer. Our
central hypothesis is that ARID1A-mutated ovarian cancer can be therapeutically eradicated by the
combination of a clinically applicable glutaminase inhibitor such as CB-839 and an anti-PD-L1 immune
checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism underlying the
dependence of ARID1A mutation on the glutamine metabolism; and Aim 2 will develop a novel therapeutic
approach for ARID1A-mutated ovarian cancer by combining a clinically applicable glutaminase inhibitor and
anti-PD-L1. The proposed studies are highly innovative because they challenge current research/clinical
paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian
cancers. The research proposed is of high impact because it will provide a scientific rationale for developing
urgently needed novel therapeutic strategies by repurposing the clinically applicable glutaminase inhibitor CB-
839 and an FDA-approved immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that
currently has no effective therapy. Since ARID1A is the most frequently mutated epigenetic regulator across
human cancers, the mechanistic insights gained from the current studies will have broad implications for many
different types of cancers as well.

## Key facts

- **NIH application ID:** 10378985
- **Project number:** 1R01CA260661-01A1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Rugang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $184,954
- **Award type:** 1
- **Project period:** 2022-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378985

## Citation

> US National Institutes of Health, RePORTER application 10378985, Metabolic basis of ARID1A-mutated ovarian cancer (1R01CA260661-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378985. Licensed CC0.

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