# Targeting EZH2 in CARM1-expressing epithelial ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $142,340

## Abstract

Project Summary
 Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the United States.
Thus, there is an urgent need to develop new therapeutic approaches for this disease. EOC is
genetically heterogeneous and, therefore, it is imperative that therapeutic strategies be personalized by
targeting distinct molecular subsets of EOC. CARM1 is an arginine methyltransferase that
asymmetrically dimethylates protein substrates on arginine residues. Notably, EOC is among the cancer
types that show the highest CARM1 amplification rates in The Cancer Genome Atlas (TCGA) database.
The role of CARM1 in EOC has never been investigated. The ultimate goal of the current proposal is to
develop novel approaches to treat and eradicate CARM1-associated EOC. Our unbiased screen show
that CARM1-expressing EOC cells are selectively sensitive to the inhibition of EZH2, another epigenetic
regulator. Genome-wide profiling suggests that the observed selectivity correlates with upregulation of
EZH2 target genes in a CARM1-dependent manner. Inactivation of subunits of the SWI/SNF chromatin-
remodeling complex is synthetically lethal with inhibition of EZH2. Interestingly, BAF155, a core subunit
of the SWI/SNF complex, is a substrate of CARM1. Indeed, our preliminary data support a model that
CARM1 renders cells functionally dependent on EZH2 activity by methylating BAF155. CARM1
expression is typically mutually exclusive with BRCA1/2 mutations in EOC. PARP inhibitor Olaparib is
approved by FDA for recurrent BRCA1/2-mutated EOC. Thus, sensitizing BRCA1/2 wildtype EOC to
PARP inhibition remains an unmet clinical need. Notably, our preliminary data suggest a synergy
between EZH2 inhibitor and PARP inhibitor in a CARM1-dependent manner. Further, EZH2 inhibition
enhances CD8+ effector T cell trafficking into tumors by upregulating Th1-type chemokines. This raises
the possibility of combining EZH2 inhibitor with immuno-checkpoint blockade such as anti-PD-L1 therapy
in CARM-expressing EOCs. Thus, our central hypothesis is that CARM1-expressing EOC can be treated
and ultimately eradicated by targeting EZH2 in combination with PARP inhibitor or immune-checkpoint
blockade such as anti-PD-L1 therapy. Two specific aims are proposed: Aim 1: To investigate the
mechanistic basis underlying the selectivity of EZH2 inhibition against CARM1; and Aim 2: To develop
novel therapeutic strategies for CARM1-expressing EOC. The proposed studies are highly innovative
because they challenge current research/clinical paradigms, and explore new intervention strategies for
CARM1-associated EOC. The research proposed is of high impact because it has the potential to
establish the first effective combinational therapeutic strategy for CARM1-associated EOC. Since
amplification and overexpression of CARM1 occurs in several other major cancer types, the mechanistic
insights gained from the current studies will also have broad implications.

## Key facts

- **NIH application ID:** 10814615
- **Project number:** 7R01CA163377-11
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Rugang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $142,340
- **Award type:** 7
- **Project period:** 2012-08-18 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814615

## Citation

> US National Institutes of Health, RePORTER application 10814615, Targeting EZH2 in CARM1-expressing epithelial ovarian cancer (7R01CA163377-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814615. Licensed CC0.

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