Role of EZH2 as a Driver and Therapeutic Target of Hepatocellular Carcinoma

EZH2 作为肝细胞癌驱动因素和治疗靶点的作用

• 批准号: 10587023
• 负责人: MICHELLE ALICE KELLIHER
• 金额: $ 47.89万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587023
• 关键词: Accounting; Agar; American; Antineoplastic Agents; CXCL10 gene; Carcinoma; Catalytic Domain; Cell Proliferation; Cell model; Cell surface; Cells; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complex; Cultured Cells; DUSP6 protein; Development; Drug Targeting; EZH2 gene; Ectopic Expression; Epigenetic Process; Epithelioid Sarcomas; Experimental Models; Follicular Lymphoma; Gene Silencing; Genes; Growth; Human; Immune system; Ligands; Liver; MAPK3 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mitogen-Activated Protein Kinases; Molecular; Mus; Mutate; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Poly(ADP-ribose) Polymerase Inhibitor; Polycomb; Primary carcinoma of the liver cells; Proteins; Publishing; Regimen; Repression; Role; Sampling; Solid Neoplasm; Testing; Treatment Efficacy; Tumor Immunity; Tumor Promotion; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Vascular Endothelial Growth Factors; Xenograft procedure; bevacizumab; cell motility; chemokine; clinically relevant; effective therapy; epigenetic silencing; experimental study; hepatocellular carcinoma cell line; histone methyltransferase; humanized monoclonal antibodies; humanized mouse; inhibitor; knock-down; liver cancer model; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; programmed cell death ligand 1; small molecule; small molecule inhibitor; therapeutic target; tumor; tumor eradication; tumor growth

PROJECT SUMMARY Hepatocellular carcinoma (HCC) accounts for over 30,000 deaths annually in the United States and current therapies provide negligible clinical benefit. Factors that epigenetically silence HCC tumor suppressor genes are expected to promote tumor development and thus may provide novel therapeutic targets. The histone methyltransferase EZH2 is the catalytic subunit of polycomb repressive complex 2 (PRC2), a master regulator of epigenetic silencing. EZH2 is mutated or overexpressed in a variety of malignancies and has been shown to function as an oncogene in some cancers. Efficacious small molecule inhibitors of EZH2 have been developed and have shown promising results in clinical trials for certain EZH2-driven cancers and recently received FDA approval for the treatment of epithelioid sarcoma and follicular lymphoma. Based upon analysis of HCC patient samples, and experiments involving cultured HCC cells and mouse models of HCC, we have found that EZH2 is an HCC oncogene that is an intrinsic driver of tumor development. This intrinsic oncogenic activity of EZH2 is due, at least in part, to epigenetic silencing of an ERK-specific phosphatase, DUSP6, resulting in activation of a mitogen-activated protein (MAP) kinase pathway that stimulates cellular proliferation. Furthermore, we have demonstrated, in two published studies from our group, that EZH2 suppresses the ability of natural killer (NK) cells to eradicate cultured HCC cells by epigenetically silencing the gene encoding ULBP1, a tumor cell-surface activating ligand for NK cells, and suppresses NK cell migration to HCC cells by epigenetically silencing the gene encoding the chemokine CXCL10. Thus, our published and preliminary results suggest that EZH2 drives HCC tumor development through both a cell intrinsic mechanism (activation of a MAP kinase pathway that stimulates cellular proliferation) and a cell extrinsic mechanism (inhibition of NK cell-mediated tumor eradication). In this application our objectives are to establish these two roles of EZH2 in HCC mouse models, determine the molecular pathways through which EZH2 promotes tumor growth, and evaluate EZH2 as an HCC drug target. In specific aim 1, we will establish that EZH2 promotes HCC tumor growth by suppressing NK cell-mediated anti- tumor immunity in humanized mice, and define the roles of CXCL10 and ULBP1 as critical EZH2 targets whose epigenetic silencing suppresses NK cell-mediated eradication of HCC. In specific aim 2, we will establish DUSP6 as a critical EZH2 target gene whose epigenetic silencing promotes HCC tumor growth through increased ERK1/2 phosphorylation. In specific aim 3, we will evaluate pharmacological inhibition of EZH2 alone and in combination with other anti-cancer agents as a potential HCC therapy. Collectively, the results of the experiments proposed in this application will elucidate the cell intrinsic and cell extrinsic pathways through which EZH2 promotes HCC tumor growth, and evaluate new therapeutic approaches for HCC.

项目总结 在美国，每年有超过30,000人死于肝细胞癌，目前 治疗提供的临床益处微乎其微。抑制肝癌抑癌基因的表观遗传因素有 有望促进肿瘤的发展，从而可能提供新的治疗靶点。组蛋白 甲基转移酶EZH2是多梳抑制复合体2(PRC2)的催化亚单位，它是一个主调节因子 表观遗传沉默。EZH2在多种恶性肿瘤中发生突变或过度表达，并已被证明 在某些癌症中起致癌基因的作用。已开发出有效的EZH2小分子抑制剂 并在某些由EZH2驱动的癌症的临床试验中显示出有希望的结果，最近获得了FDA 批准用于治疗上皮样肉瘤和滤泡性淋巴瘤。基于对肝细胞癌患者的分析 样本，以及培养的肝癌细胞和小鼠肝癌模型的实验，我们发现EZH2 是一种肝癌癌基因，是肿瘤发展的内在驱动因素。EZH2的这种内在致癌活性是 至少部分是由于ERK特异性磷酸酶DUSP6的表观遗传沉默导致了一种 刺激细胞增殖的丝裂原活化蛋白(MAP)激酶途径。此外，我们还拥有 在我们小组发表的两项研究中，证明了EZH2抑制自然杀伤(NK)的能力 通过表观遗传沉默肿瘤细胞表面编码ULBP1的基因来根除培养的肝癌细胞 激活NK细胞的配体，并通过表观遗传沉默抑制NK细胞向肝癌细胞的迁移 编码趋化因子CXCL10。因此，我们发表的和初步的结果表明，EZH2推动了肝细胞癌 肿瘤的发展既通过细胞内在机制(激活刺激MAPK通路 细胞增殖)和细胞外在机制(抑制NK细胞介导的肿瘤根除)。在这 应用我们的目标是在肝癌小鼠模型中建立EZH2的这两个角色，确定EZH2的 EZH2促进肿瘤生长的分子途径，并评价EZH2作为肝癌药物靶点。 在特定的目标1中，我们将建立EZH2通过抑制NK细胞介导的抗肿瘤生长来促进肝癌的生长 在人源化小鼠中的肿瘤免疫，并确定CXCL10和ULBP1作为其关键的EZH2靶点的作用 表观遗传沉默抑制NK细胞介导的肝癌根除。在具体目标2中，我们将建立DUSP6 作为一个关键的EZH2靶基因，其表观遗传沉默通过增加 ERK1/2磷酸化。在具体目标3中，我们将单独评估EZH2的药理抑制作用 与其他抗癌药物联合作为一种潜在的肝癌治疗方法。总的来说，这些实验的结果 在本应用中提出的将阐明EZH2通过的细胞内和细胞外途径 促进肝细胞癌肿瘤生长，评估肝细胞癌新的治疗方法。