# Epigenetic Synergy Between DNMT and EZH1/2 Inhibitors for Therapy in Solid Tumors

> **NIH NIH P50** · CORIELL INSTITUTE FOR MEDICAL RESEARCH · 2022 · $446,575

## Abstract

PROJECT SUMMARY
DNA methyltransferase inhibitors (DNMTi), such as the FDA-approved nucleoside analog 5-aza-2'-deoxycytidine
(DAC), are currently the only available clinical drugs that can reverse abnormal DNA methylation in cancer cells
and have emerged as a potential means to increase the efficacy of immunotherapy in cancer. However, the DNA
de-methylation utility of these agents, particularly in solid tumors, does not attain the desired downstream
transcriptional consequences seen in preclinical models. As such, novel therapeutic strategies to regulate DNMT
activity are urgently needed and are directly addressed in this SPORE project. Our preliminary data shows that
several clinically applied EZH1/2 inhibitors block compensatory repressive activity of PRC2 at select tumor
suppressor genes and repeat elements consequent to DNA methylation removal by DAC. Blocking this
repressive “epigenetic switch,” which we propose is a key contributor to DNMTi resistance seen in patients
treated with these drugs, may underlie an observed synergy of DNMTi+EZH1/2i to de-repress cancer-associated
genic and intergenic transcriptional silencing. Our overall goal is to define mechanisms of transcriptional synergy
and immune crosstalk consequent to DNMTi+EZH1/2i and evaluate the clinical potential of this epigenetic
therapeutic combination, alone, and as a primer to immunotherapy. To this end, we will (Aim 1) define cancer
cell-intrinsic chromatin regulatory mechanisms and cellular pathways involved in the molecular and therapeutic
effects of combined EZH1/2 and DNMT inhibition. Concurrently, we will (Aim 2) determine in mouse models of
checkpoint therapy resistant disease, the antitumor effects of combined EZH1/2 and DNMT inhibition on cancer
vs. immune cells and those dependent on interactions between the two. In addition, a proposed Phase 1 clinical
trial, inclusive of extensive correlative science endpoints, will (Aim 3) validate the impact of combination EZH1/2
and DNMT inhibitor therapy on immune-response gene signaling circuits and the tumor microenvironment across
multiple solid tumor types. Impacts of our studies include: 1) defining exploitable mechanisms of molecular
crosstalk associated with DNMTi therapy; 2) enabling effective clinical application of DNMTi+EZH1/2i therapy;
3) revealing correlative biomarkers to assess drug action in patient tumors; and 4) expanding opportunities for
checkpoint and targeted immunotherapy combinations.

## Key facts

- **NIH application ID:** 10470366
- **Project number:** 5P50CA254897-02
- **Recipient organization:** CORIELL INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Scott Rothbart
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,575
- **Award type:** 5
- **Project period:** 2021-08-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470366

## Citation

> US National Institutes of Health, RePORTER application 10470366, Epigenetic Synergy Between DNMT and EZH1/2 Inhibitors for Therapy in Solid Tumors (5P50CA254897-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470366. Licensed CC0.

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