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

• 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
• 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

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.

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