# Project 3: Induction of synthetic lethality with combined DNMT and PARP inhibition

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $362,734

## Abstract

PROJECT SUMMARY
Recent data have shown that PARP inhibitors are an effective therapeutic strategy for DNA repair-deficient
metastatic castration-resistant prostate cancer (mCRPC). The response rates to PARP inhibition have been
most pronounced in patients with a homologous recombination deficiency (HRD) alteration, specifically BRCA1
or BRCA2 mutations. Since only 10-20% of mCRPC patients harbor sensitizing HRD mutations, the group of
men that may potentially benefit from this therapy is limited. Novel strategies to unlock the utility of PARP
inhibitors for treatment of patients that lack HRD defects would therefore have tremendous impact in the
treatment of advanced prostate cancer. Based on our strong preliminary data, here we will test the innovative
hypothesis that the combination of DNA methyltransferase inhibitors (DNMTi) and poly-ADP ribose polymerase
inhibitors (PARPi) will produce a “triple-threat” to cancer cells by inducing synthetic lethality even in HR-
proficient mCRPC patients via any of three complementary mechanisms: i) DNMTi-mediated downregulation of
homologous recombination coupled with synergistic generation of DNA damage with both drugs, each trapping
their target enzyme on DNA; ii) epigenetic and DNA damage mediated activation of immunogenic interferon
pathways to promote anti-tumor immune responses; and iii) inhibition of AR signaling, which remains vital to
support growth and survival of mCRPC. We will determine the utility and safety of this combination in different
subtypes of prostate cancer using multiple prostate cancer pre-clinical models in vitro and in vivo (Aim 1),
determine the mechanisms by which the combination induces synthetic lethality in mCRPC (Aim 2), and carry
out a pharmacodynamic biomarker-driven phase 1/1b clinical trial of the combination in men with advanced
mCRPC (Aim 3). If successful, these studies will yield a powerful new therapeutic strategy for mCRPC and
expand the utility of PARPi to men without underlying HRD mutations.

## Key facts

- **NIH application ID:** 10769307
- **Project number:** 1P50CA272391-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Srinivasan Yegnasubramanian
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,734
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769307

## Citation

> US National Institutes of Health, RePORTER application 10769307, Project 3: Induction of synthetic lethality with combined DNMT and PARP inhibition (1P50CA272391-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10769307. Licensed CC0.

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