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

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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.