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

DNMT 和 EZH1/2 抑制剂在实体瘤治疗中的表观遗传协同作用

基本信息

批准号：
10696170
负责人：
Scott Rothbart
金额：
$ 44.66万
依托单位：
CORIELL INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696170
关键词：
Address Adoptive Transfer Antibodies Antigen Presentation Pathway Antitumor Response Behavior Biological Markers Cancer cell line Cell Separation Cell surface Cells Chemicals Chromatin Clinical Clinical Management Clinical Research Colon Adenocarcinoma Colon Carcinoma Colorectal Cancer Combination immunotherapy Combined Modality Therapy Comparative Study Cytidine Deaminase Inhibitor DNA DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Deoxycytidine Disease Resistance EZH2 gene Elements Endogenous Retroviruses Enrollment Epigenetic Process Excision FDA approved Gene Expression Gene Silencing Genes Genetic Genetic Transcription Goals Growth Human Immune Immune Evasion Immune Response Genes Immune signaling Immunologics Immunotherapy Inflammasome Interferons Malignant Neoplasms Malignant neoplasm of lung Methods Modification Molecular Mus Nature Non-Small-Cell Lung Carcinoma Oncogenic Oral Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Population Pre-Clinical Model Probability Publishing Refractory Resistance Sampling Science Signal Transduction Solid Neoplasm Testing Therapeutic Therapeutic Effect Therapeutic Intervention Toxic effect Tumor Suppressor Genes Viral Work antitumor effect cancer cell cancer subtypes checkpoint therapy clinical application clinical subtypes combinatorial defense response demethylation derepression design disease classification drug action epigenetic drug epigenetic therapy epigenomics health management immune cell infiltrate immune modulating agents improved inhibitor inhibitor therapy lung cancer cell mouse model novel novel therapeutic intervention nucleoside analog pressure programmed cell death protein 1 programs response stem synergism targeted treatment trial design tumor tumor microenvironment

项目摘要

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.

项目总结