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-项目摘要 这个新的计划项目（P01）提案的总体目标是产生高度协作和集成的 对EB病毒引起的上皮癌的紧急，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20万例新癌症病例有因果关系。EB病毒上皮 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。EB病毒通过这些机制有助于这些 上皮癌仍然难以捉摸，迄今为止，没有FDA批准的病毒特异性疗法， 治疗感染EB病毒的癌症。我们已经组建了一个EB病毒研究团队， 肿瘤病毒学和癌症生物学的互补方面，在病毒遗传学的特定领域感兴趣， 表观遗传学、代谢、药物发现和EBV致癌模型。项目团队将合作 在一个协调的战略，以确定关键的病毒和细胞的脆弱性，在EB病毒上皮癌， 用于治疗干预。该计划将测试中心假设，即EBV癌症发生在 改变EBV潜伏期和致癌性的代谢和表观遗传途径中的体细胞突变背景，以及 这种病毒-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 我们提出了三个项目和三个科学核心，以解决以下问题：（1）确定EBV如何 在上皮癌细胞中建立潜伏性和致癌性感染（2）确定EBV潜伏性 感染驱动表观遗传和代谢变化，包括CpG岛甲基化因子的形成 表型（CIMP）促进上皮细胞肿瘤发生。(3)利用机械见解来开发 治疗EBV上皮癌的新治疗策略。这3个项目主要关注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 甲硫氨酸代谢（Gewurz）。这三个科学核心支持生物信息学，药物发现和模型。 EBV癌症作为研究促进剂支持3个项目中的每一个。这个团队和项目将共同 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 治疗策略是病毒特异性和精确的医学。