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：
10269644
负责人：
Scott Rothbart
金额：
$ 43.22万
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/10269644
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 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 Infiltration Inflammasome Interferons Lead Malignant Neoplasms Malignant neoplasm of lung Methods Methylation 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 Repression Resistance Sampling Science Signal Transduction Solid Neoplasm Testing Therapeutic Therapeutic Effect Therapeutic Intervention Toxic effect Tumor Suppressor Genes Tumor-infiltrating immune cells Viral Work antitumor effect base cancer cell cancer subtypes checkpoint therapy clinical application clinical subtypes combinatorial defense response demethylation design drug action epigenetic therapy epigenomics health management improved inhibitor/antagonist 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.

项目摘要 DNA甲基转移酶抑制剂（DNMTI），例如FDA批准的核外侧类似物5-aza-2'-脱氧胞苷（DAC）目前是唯一可以逆转癌细胞中DNA甲基化异常DNA甲基化的临床药物并成为提高癌症免疫疗法效率的潜在手段。但是，DNA 这些药物的去甲基化效用，特别是在实体瘤中，无法达到所需的下游在临床前模型中看到的转录后果。因此，调节DNMT的新型治疗策略迫切需要活动，并在此孢子项目中直接解决。我们的初步数据表明几种临床应用的EZH1/2抑制剂阻止了PRC2在选定肿瘤上的补偿反射活性 DAC抑制基因和重复元素造成DNA甲基化的去除。阻止这个抑制性“表观遗传转换”，我们建议的是患者中DNMTI耐药性的关键因素用这些药物治疗，可能是DNMTI+EZH1/2I与抑制相关的dnmti+Ezh1/2i的协同作用的基础基因和基因间转录沉默。我们的总体目标是定义转录协同的机制与DNMTI+EZH1/2I相关的免疫刺激性单独的治疗组合，作为免疫疗法的介绍。为此，我们将（AIM 1）定义癌症细胞中性染色质调节机制和分子和治疗中涉及的细胞途径 EZH1/2和DNMT抑制的效果。同时，我们将（AIM 2）在鼠标模型中确定检查点抗病性疾病，EZH1/2和DNMT抑制对癌症的抗肿瘤作用与免疫细胞以及依赖两者之间相互作用的细胞。另外，提出的1阶段临床包括广泛相关科学终点的试验将（AIM 3）验证组合EZH1/2的影响和DNMT抑制剂治疗在免疫反应基因信号通路和遍历肿瘤微环境的抑制剂治疗多种实体瘤类型。我们研究的影响包括：1）定义分子的可利用机制与DNMTI治疗相关的串扰； 2）实现DNMTI+EZH1/2I治疗的有效临床应用； 3）揭示相关生物标志物评估患者肿瘤的药物作用； 4）扩大机会检查点和靶向免疫疗法组合。