Epigenomic Drivers of EBV Epithelial Cancers

EB 病毒上皮癌的表观基因组驱动因素

基本信息

批准号：
10627690
负责人：
PAUL M LIEBERMAN
金额：
$ 46.97万
依托单位：
WISTAR INSTITUTE
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：
2023-05-11 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627690
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine 3-Dimensional ARID1A gene Accounting Affect Automobile Driving Carcinoma Chromosomes Collaborations CpG Islands DNA Binding DNA Crosslinking DNA Damage DNA Methylation Epigenetic Process Episome Epithelial Cells Epithelium Epstein-Barr Virus latency Genes Genetic Transcription Genome Goals Human Herpesvirus 4 Investigation LMP1 Lytic Maintenance Malignant Neoplasms Medical Metabolic Metabolic Control Methylation Molecular Conformation Mutation Nasopharynx Carcinoma Oncogenic PIK3CA gene PIK3CG gene Pathway interactions Phenotype Proteins Regulatory Element Repression Role Site Stomach Carcinoma Stress Testing Transcriptional Regulation Transcriptional Silencer Elements Viral Viral Genome Viral Oncogene Virus Virus Latency Work carcinogenesis epigenome epigenomics inhibitor insight latent infection methylation pattern mouse model novel therapeutic intervention replication stress response small molecule inhibitor therapeutic evaluation therapeutic target

项目摘要

PROJECT 1 – PROJECT SUMMARY The long-term goal of this project is to determine how EBV establishes an oncogenic latent epigenome in EBV- associated epithelial cancers and to leverage this information to develop new therapeutic strategies to target EBV latent infection in epithelial cancers. All EBV cancers share the common feature of maintaining latent viral genomes that express a restricted subset of viral oncogenes. EBV epithelial cancers also have the distinguishing feature of CpG Island Methylation Phenotype (CIMP). The role of EBV latent infection in driving CIMP, and the role of CIMP in regulating oncogenic EBV latency are not fully elucidated, but critical for understanding EBV carcinogenesis. In Aim 1, we propose to investigate how EBV latent infection promotes CIMP. We will test the specific hypothesis that EBNA1-driven episome maintenance induces a PARP1-dependent DNA-damage response that drives CIMP. In collaboration with Project 2, we will investigate the role of PARP1 and UHRF1 in the formation of site-specific viral and host DNA methylation. In collaboration with Project 3, we will explore the role of PI3K activation in controlling replication stress in epithelial cancers. In Aim 2, we will test the hypothesis that CIMP and other somatic changes, such as PI3K and ARID1A mutations, facilitate the formation of a viral type II latency. In collaboration with Project 2, we will examine the role of CTCF and CIMP on EBV 3D conformation. With Project 3, we will investigate how metabolic changes favor establishment of type II latency in epithelial cancers. Finally, we will work in collaboration with Projects 2, 3 and all Cores to identify new therapeutic approaches to treat EBV(+) epithelial cancers. To this end, we have developed new small molecule inhibitors and mouse models of EBV epithelial cancers to better understand these mechanisms and test therapeutic strategies. The overarching hypothesis of Project 1 is that EBV epithelial malignancies depend on the establishment of a distinct epigenetic state involving CpG methylator phenotype (CIMP) and that key regulators of this epigenetic state are therapeutic targets in EBV epithelial carcinogenesis.

项目 1 – 项目摘要该项目的长期目标是确定 EBV 如何在 EBV- 中建立致癌的潜在表观基因组。相关的上皮癌，并利用这些信息来开发新的治疗策略上皮癌中的 EBV 潜伏感染所有 EBV 癌症都具有维持潜伏病毒的共同特征。表达有限的病毒癌基因子集的基因组也具有独特的特征。 CpG岛甲基化表型（CIMP）的特征以及EBV潜伏感染在驱动CIMP中的作用。 CIMP 在调节致癌 EBV 潜伏期中的作用尚未完全阐明，但对于了解 EBV 至关重要在目标 1 中，我们建议研究 EBV 潜伏感染如何促进 CIMP。 EBNA1 驱动的附加体维持诱导 PARP1 依赖性 DNA 损伤的具体假设与项目 2 合作，我们将研究 PARP1 和 UHRF1 在其中的作用。与项目 3 合作，我们将探索位点特异性病毒和宿主 DNA 甲基化的形成。 PI3K 激活在控制上皮癌复制应激中的作用在目标 2 中，我们将检验该假设。 CIMP 和其他体细胞变化，例如 PI3K 和 ARID1A 突变，促进病毒的形成与项目 2 合作，我们将研究 CTCF 和 CIMP 在 EBV 3D 上的作用。在项目 3 中，我们将研究代谢变化如何有利于 II 型潜伏期的建立。最后，我们将与项目 2、3 和所有核心合作来发现新的。治疗 EBV(+) 上皮癌的治疗方法为此，我们开发了新的小分子。 EBV 上皮癌抑制剂和小鼠模型，以更好地了解这些机制并进行测试项目 1 的总体治疗假设是 EBV 上皮恶性肿瘤。取决于涉及 CpG 甲基化表型 (CIMP) 的独特表观遗传状态的建立这种表观遗传状态的关键调节因子是 EBV 上皮癌发生的治疗靶点。