Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers

针对 EB 病毒上皮癌的表观遗传和代谢控制

基本信息

批准号：
10627689
负责人：
PAUL M LIEBERMAN
金额：
$ 243.61万
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/10627689
关键词：
ARID1A gene Aberrant DNA Methylation Address Animal Model Area Basic Science Bioinformatics Biometry CRISPR/Cas technology Cancer Biology Cancer Etiology Carcinoma Cessation of life Chemicals Collaborations Combined Modality Therapy Complex CpG Island Methylator Phenotype DNA Damage DNA Methylation Dependence Development Diagnosis Drug Modelings Enhancers Epigenetic Process Episome Epithelial Cells Epstein-Barr Virus Infections Epstein-Barr Virus latency FDA approved Failure Genomics Goals Human Herpesvirus 4 Immunotherapy Individual Infection Institution Integration Host Factors Latent virus infection phase Link Maintenance Malignant Neoplasms Mediating Medical Metabolic Metabolic Control Metabolism Methionine Metabolism Pathway Methodology Modeling Nasopharyngeal Undifferentiated Carcinoma Nasopharynx Carcinoma Oncogenic Oncology Organoids PIK3CA gene Pathway interactions Patient Care Pharmaceutical Chemistry Precision therapeutics Process Refractory Relapse Research Research Personnel Resistance Somatic Mutation Stomach Carcinoma Testing Therapeutic Therapeutic Intervention Translational Research Treatment Failure Viral Virus Latency Xenograft procedure cancer cell cancer therapy carcinogenesis computerized data processing drug discovery epigenome gastric organoids high throughput screening improved in vitro testing in vivo Model inhibitor innovation insight interdisciplinary approach interest latent infection malignant stomach neoplasm molecular subtypes mortality mutant novel strategies novel therapeutic intervention patient derived xenograft model precision medicine programs response skills targeted treatment tool transcriptome tumor tumor metabolism tumorigenesis virology virus genetics

项目摘要

OVERALL – PROJECT SUMMARY The overall aim of this new Program Project (P01) proposal is to generate highly collaborative and integrated basic and translational research on the urgent, unmet medical need of epithelial cancers caused by Epstein-Barr Virus (EBV). EBV latent infection is causally linked to over 200,000 new cancer cases per year. EBV epithelial cancers represent over 75% of all EBV cancers with highest mortality rates and treatment failures. EBV- associated gastric carcinoma (EBVaGC) and nasopharyngeal carcinoma (NPC) have many similarities with respect to viral latency and oncogenic transformation. The mechanisms through which EBV contributes to these epithelial cancers remains elusive, and to date, there are no viral-specific therapies that are FDA approved to treat cancers infected with EBV. We have assembled a team of EBV investigators with expertise in complementary aspects of tumor virology and cancer biology, with specific areas of interest in viral genetics, epigenetics, metabolism, drug discovery, and models of EBV carcinogenesis. The Program team will collaborate in a coordinated strategy to identify key viral and cellular vulnerabilities in EBV epithelial cancers that can be targeted for therapeutic intervention. The Program will test the central hypothesis that EBV cancers arise in the context of somatic mutations in metabolic and epigenetic pathways that alter EBV latency and oncogenicity, and how this viral-host co-dependency provides therapeutic opportunities. To achieve these goals for the Program we propose three Projects and three scientific Cores to address the following: (1) Determine how EBV establishes a latent and oncogenic infection in epithelial cancer cells (2) Determine how EBV latent infection drives epigenetic and metabolic shifts including the formation of CpG island methylator phenotype (CIMP) to promote epithelial cell oncogenesis. (3) Leverage mechanistic insights to develop new therapeutic strategies to treat EBV epithelial cancers. The 3 Projects focus broadly on EBV latency and epigenome (Lieberman), PARP, NAD and DNA damage metabolism (Tempera), and DNA methylation and methionine metabolism (Gewurz). The 3 scientific Cores support bioinformatics, drug discovery, and models of EBV cancers to support each of the 3 Projects as research enhancers. Together, this team and Program will investigate key features of EBV cancer mechanisms, build new tools to study EBV cancers, and develop new therapeutic strategies that are viral-specific and precision-based medicine.

总体而言——项目概要这个新计划项目 (P01) 提案的总体目标是产生高度协作和集成的针对 Epstein-Barr 引起的上皮癌的紧迫且未满足的医疗需求的基础和转化研究病毒 (EBV)。EBV 潜伏感染与每年超过 200,000 例新的 EBV 上皮癌病例有因果关系。癌症占所有 EBV 癌症的 75% 以上，死亡率和治疗失败率最高。相关胃癌（EBVaGC）和鼻咽癌（NPC）有许多相似之处关于病毒潜伏期和致癌转化的机制。上皮癌仍然难以捉摸，迄今为止，还没有 FDA 批准的病毒特异性疗法我们组建了一支具有 EBV 专业知识的研究团队。肿瘤病毒学和癌症生物学的互补方面，以及病毒遗传学的特定领域，该项目团队将在表观遗传学、新陈代谢、药物发现和 EBV 致癌模型方面进行合作。采取协调一致的策略来识别 EBV 上皮癌中的关键病毒和细胞脆弱性，这些脆弱性可以该计划将测试 EBV 癌症发生于人体的中心假设。代谢和表观遗传途径中体细胞突变改变 EBV 潜伏期和致癌性的背景，以及这种病毒与宿主的相互依赖性如何提供治疗机会以实现该计划的这些目标。我们提出三个项目和三个科学核心来解决以下问题：(1) 确定 EBV 如何在上皮癌细胞中建立潜伏的致癌感染 (2) 确定 EBV 潜伏的方式感染驱动表观遗传和代谢变化，包括 CpG 岛甲基化的形成（3）利用机制洞察来发展治疗 EBV 上皮癌的新治疗策略这 3 个项目广泛关注 EBV 潜伏期。和表观基因组 (Lieberman)、PARP、NAD 和 DNA 损伤代谢 (Tempera) 以及 DNA 甲基化和蛋氨酸代谢 (Gewurz) 的 3 个科学核心支持生物信息学、药物发现和模型。 EBV 癌症将作为研究增强剂共同支持这 3 个项目。研究 EBV 癌症机制的关键特征，建立研究 EBV 癌症的新工具，并开发新的病毒特异性和精准医学的治疗策略。