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

• 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
• 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

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 例新癌症病例有因果关系。 EB病毒上皮细胞 癌症占所有 EBV 癌症的 75% 以上，死亡率和治疗失败率最高。 EB病毒- 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。 EBV 促成这些的机制 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 治疗感染 EB 病毒的癌症。我们组建了一支由 EBV 研究人员组成的团队，他们具有以下方面的专业知识： 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， 表观遗传学、代谢、药物发现和 EBV 致癌模型。计划团队将协作 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 有针对性的治疗干预。该计划将检验 EB 病毒癌症发生于 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。为了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 表型（CIMP）促进上皮细胞肿瘤发生。 （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 延迟 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（琼瑶浆）。 3 个科学核心支持生物信息学、药物发现和模型 EBV 癌症作为研究增强剂支持这 3 个项目。该团队和计划将共同努力 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。