# Protein arginine methyltransferase inhibitors in treatment of high-grade serous ovarian cancer and triple-negative breast cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $530,697

## Abstract

PROJECT SUMMARY
The expression levels of protein arginine methyltransferases (PRMTs) are significantly elevated in cancer cells
and are associated with poor clinical outcomes. This strongly suggests their potential as a novel class of
therapeutic targets in oncology. Major pharmaceutical companies have developed over ten selective and potent
PRMT inhibitors (PRMTis) that are currently in early-stage clinical evaluation. However, due to the understudied
nature of arginine methylation as a post-translational modification, a comprehensive mechanistic understanding
of PRMT functions in cancer is urgently needed to enable the clinical application of these inhibitors. Notably,
recent clinical trial results indicate that the activity of PRMTis alone may be insufficient for effective cancer
management in patients. Therefore, it is imperative to conduct mechanism-driven preclinical evaluations of
combination strategies that target PRMTs alongside other therapeutic drugs to achieve clinical success. Both
high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) share clinical and
genomic characteristics such as poor prognosis, homologous recombination deficiency, and potential
immunoreactivity. Given the urgent unmet medical need to develop effective therapeutic strategies for these
diseases, our preliminary studies have merged large-scale drug combination screening and cancer genomic
profiling to establish a strong rationale for applying PRMTis in treating HGSOC and TNBC. Our hypothesis is
that because of uncontrolled proliferation, increased DNA damage, and activated oncogenes, cancer cells must
sustain abnormal levels of transcription, splicing, and protein arginine methylation through enhanced PRMT
activities (PRMT addiction). Treatment with PRMTis can disrupt the hyperactivated PRMT-regulome that enables
cancer cells to survive. We've assembled a team of investigators with diverse expertise and resources to test
this hypothesis through three specific aims: Specific Aim 1: Characterize molecular mechanisms of PRMTi mono-
and combination therapies; Specific Aim 2: Evaluate therapeutic potentials of PRMTis in HGSOC and TNBC
preclinical models; and Specific Aim 3: Investigate effects of PRMTi treatments on anti-tumor immune responses.
The overarching objective of this application is to systematically explore the dynamic changes in the regulome
induced by PRMTi treatments in cancer cells. This will offer fresh insights into their mechanisms of action and
provide a rationale for the clinical development of PRMTi mono- and combination therapies in the field of
oncology.

## Key facts

- **NIH application ID:** 10976793
- **Project number:** 1R01CA285598-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,697
- **Award type:** 1
- **Project period:** 2024-08-29 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976793

## Citation

> US National Institutes of Health, RePORTER application 10976793, Protein arginine methyltransferase inhibitors in treatment of high-grade serous ovarian cancer and triple-negative breast cancer (1R01CA285598-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10976793. Licensed CC0.

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