Harnessing double stranded-RNA (dsRNA)-response and anti-tumor effect in PRC2-inactivated cancer

利用双链 RNA (dsRNA) 反应和 PRC2 失活癌症的抗肿瘤作用

基本信息

批准号：
10638759
负责人：
Ping Chi
金额：
$ 74.5万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-22 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638759
关键词：
Alleles Antitumor Response Autophagocytosis Biochemical C57BL/6 Mouse Cancer Model Cells Chromatin Structure Clinical Trials Complex DNA Modification Methylases Data Decitabine Development Double-Stranded RNA EZH2 gene Engineering Engraftment Evaluation Evolution Future Generations Genetic Genetic Transcription Genome Goals High Prevalence Histone H3 IRF3 gene Immune Immune response Immunocompetent Immunologic Cytotoxicity Immunotherapy In Vitro Individual Infection Innate Immune Response Lysine Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Mus NF-kappa B Neurofibrosarcoma Outcome Phenotype Polycomb Recombinant modified vaccinia virus Ankara Resistance Retrotransposon Role Signal Pathway Signal Transduction Soft tissue sarcoma System Therapeutic Transcriptional Activation Tumor Suppressor Proteins Virus Work antitumor effect biomarker driven cancer cell cancer type cytotoxic cytotoxicity demethylation design effective therapy epigenome histone methylation immune checkpoint blockade immunogenic immunogenicity improved outcome in vivo inhibitor innovation insight knock-down melanoma mouse model multiple omics neoplastic cell novel novel therapeutic intervention pre-clinical response sensor single-cell RNA sequencing stemness stress granule transcriptome treatment effect tumor tumor growth tumor heterogeneity tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT: The polycomb repressive complex 2 (PRC2) complex establishes and maintains di- and tri-methylation of the histone H3 at lysine 27 (H3K27me2/3) in the genome and regulates chromatin structure, transcription, cellular stemness and differentiation. PRC2 is a context-dependent tumor suppressor whose core components (e.g., EZH2, EED, or SUZ12) are inactivated in various cancer types. Among these, high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma with no effective therapies, has a high prevalence (≥80%) of biallelic inactivation of EED or SUZ12, leading to complete loss of the PRC2 function. PRC2 loss in cancer results in aberrant transcriptional activation of developmentally silenced master regulators, which leads to enhanced cellular plasticity and aberrant activation of multiple signaling pathways. We recently uncovered that PRC2 loss in cancer leads to an immune-desert tumor microenvironment and resistance to immune checkpoint blockade. Nevertheless, we observed that, in murine models of PRC2-loss MPNST and mammary tumors, response to immunotherapy can be enhanced by infection with immunogenic virus, which activates double-stranded RNA (dsRNA) signaling responses. Moreover, we have identified and validated a lethal interaction between PRC2 loss and DNA methyltransferase 1 (DNMT1) knockdown in MPNST. In vitro and in vivo treatment with a demethylating agent (decitabine) or selective DNMT1 inhibitors (GSK862, GSK032) led to enhanced cytotoxicity and antitumor effects in PRC2-loss compared to PRC2 wild-type (wt) MPNST models. Mechanistically, DNMT inhibitor (DNMTi) treatment in the PRC2-loss context amplified the expression of endogenous retrotransposons and subsequently led to activation of innate immune responses, which could be explained by retrotransposons forming dsRNA and triggering cytotoxicity via PKR-dependent dsRNA sensing. we hypothesize that PRC2 loss in cancer may create therapeutic opportunities for agents (e.g., DNMTi, synthetic dsRNA, immunogenic viruses) that activate the dsRNA signaling pathways in tumor cells to induce cytotoxicity and enhance immunogenicity. Here, we propose integrative multi-omics analysis (e.g., transcriptome, epigenome, single-cell [sc]RNA-seq and scATAC-seq) and innovative approaches (e.g., novel immunogenic viruses, a novel lineage-tracking system) to evaluate novel therapeutic strategies and their mechanisms of activating dsRNA responses and anti-tumor effects in relevant PRC2-loss cancers, focusing on specific aims: (1) dissect the molecular mechanisms that underlie the selective sensitivity to DNMTi in different PRC2-loss cancers; (2) evaluate exogenous dsRNAs as a strategy to induce cytotoxicity in PRC2-loss tumors; and (3) evaluate novel therapeutic strategies of activating dsRNA-responses in relevant cancer models. These studies will generate insights into exploiting dsRNA-sensing and activation of innate immune responses as therapeutic strategies in PRC2-loss cancers and provide the pivotal preclinical data for biomarker-driven clinical trials.

项目摘要/摘要：多梳抑制复合物 2 (PRC2) 复合物建立并维持二甲基化和三甲基化组蛋白 H3 位于基因组中的赖氨酸 27 (H3K27me2/3)，调节染色质结构、转录、细胞 PRC2 是一种背景依赖性肿瘤抑制因子，其核心成分（例如， EZH2、EED 或 SUZ12) 在多种癌症类型中失活，其中，高度恶性外周瘤。神经鞘瘤（MPNST）是一种侵袭性软组织肉瘤，目前尚无有效的治疗方法，其发病率很高。 EED 或 SUZ12 双等位基因失活的患病率（≥80%），导致 PRC2 功能完全丧失。 PRC2在癌症中的缺失导致发育沉默的主调节因子的异常转录激活，这导致细胞可塑性增强和多种信号通路的异常激活。发现癌症中 PRC2 的缺失会导致免疫沙漠肿瘤微环境和耐药性尽管如此，我们在 PRC2 缺失的小鼠模型中观察到 MPNST 和对于乳腺肿瘤，免疫治疗的反应可以通过感染免疫原性病毒来增强，此外，我们还鉴定并验证了一种双链 RNA (dsRNA) 信号反应。 MPNST 中 PRC2 缺失和 DNA 甲基转移酶 1 (DNMT1) 敲低之间的致死相互作用。使用去甲基化剂（地西他滨）或选择性 DNMT1 抑制剂（GSK862、GSK032）进行体内治疗与 PRC2 野生型 (wt) MPNST 模型相比，PRC2 缺失的细胞毒性和抗肿瘤作用增强。从机制上讲，在 PRC2 缺失的情况下，DNMT 抑制剂 (DNMTi) 治疗放大了内源性逆转录转座子，随后导致先天免疫反应的激活，这可能是这是通过逆转录转座子形成 dsRNA 并通过 PKR 依赖性 dsRNA 传感触发细胞毒性来解释的。我们发现，癌症中 PRC2 的缺失可能会为药物（例如 DNMTi、合成药物）创造治疗机会。 dsRNA，免疫原性病毒）激活肿瘤细胞中的 dsRNA 信号通路以诱导细胞毒性并增强免疫原性。在这里，我们建议综合多组学分析（例如转录组，表观基因组、单细胞 [sc]RNA-seq 和 scATAC-seq）和创新方法（例如新型免疫原性方法）病毒，一种新的谱系追踪系统）来评估新的治疗策略及其机制激活相关 PRC2 缺失癌症中的 dsRNA 反应和抗肿瘤作用，重点关注特定目标： (1) 剖析不同 PRC2 缺失中对 DNMTi 选择性敏感性的分子机制癌症；(2) 评估外源 dsRNA 作为诱导 PRC2 缺失肿瘤的细胞毒性的策略；评估相关癌症模型中激活 dsRNA 反应的新治疗策略。将产生利用 dsRNA 传感和先天免疫反应激活作为治疗的见解 PRC2 缺失癌症的策略，并为生物标志物驱动的临床试验提供关键的临床前数据。