# Molecular Determinants of Response and Resistance to EZH2 and PARP inhibition in Prostate Cancer

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2024 · $442,125

## Abstract

PROJECT SUMMARY- PROJECT 2
Castration resistant prostate cancer (CRPC) is a lethal disease. Epigenetic dysregulation, including
overexpression of the enhancer of zeste homolog 2 (EZH2) drives treatment resistance, and EZH2 inhibitors are
in clinical trials. Beyond its canonical role as a member of the PRC2 complex as a transcriptional repressor, we
previously identified a non-canonical role of EZH2 in activating AR signaling, as well as in driving lineage
plasticity and neuroendocrine prostate cancer. Current data suggests that single agent activity may be limited
and that combination strategies should be pursued. We recently discovered a novel interaction between EZH2
and DNA repair processes and a synergy between EZH2 and PARP inhibition in prostate cancer. We
hypothesize that EZH2 drives downstream molecular programs through canonical and non-canonical
mechanisms, and that these downstream effects are context dependent. Combination therapy with EZH2 and
PARP inhibition will therefore have differential biologic impact in CRPC based on the underlying genomic,
epigenomic, and phenotypic context. We will elucidate the mechanisms by which EZH2 regulates DNA repair
and define how DNA repair pathways impact EZH2 drug sensitivity. We will evaluate the biologic and clinical
impact of EZH2 and PARP inhibition across the heterogeneous spectrum of CRPC through extensive preclinical
and clinical studies. We will conduct a first-in-field, investigator-initiated clinical trial of EZH2i (tazemetostat) plus
PARPi (talazoparib) with extensive translational correlates. Results from this project will provide the basis for a
new therapeutic strategy for men with CRPC.

## Key facts

- **NIH application ID:** 10916201
- **Project number:** 5P50CA272390-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Himisha Beltran
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,125
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916201

## Citation

> US National Institutes of Health, RePORTER application 10916201, Molecular Determinants of Response and Resistance to EZH2 and PARP inhibition in Prostate Cancer (5P50CA272390-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916201. Licensed CC0.

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