Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers

总体--项目摘要 这一新计划项目(P01)提案的总体目标是产生高度协作和集成 爱泼斯坦-巴尔引起的上皮性癌症的紧急和未得到满足的医疗需求的基础和翻译研究 病毒(EBV)。EBV潜伏感染与每年20多万新的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，死亡率和治疗失败最高。EBV- 相关性胃癌(EBVaGC)和鼻咽癌(NPC)与 关于病毒潜伏和致癌转化。EBV对这些疾病的作用机制 上皮性癌症仍然难以捉摸，到目前为止，还没有FDA批准的病毒特异性治疗方法 治疗感染EB病毒的癌症。我们已经组建了一支EBV调查团队，他们具有以下专业知识 肿瘤病毒学和癌症生物学的互补方面，对病毒遗传学感兴趣的特定领域， 表观遗传学、新陈代谢、药物发现和EB病毒致癌模型。计划团队将进行协作 在一项确定EBV上皮癌关键病毒和细胞脆弱性的协调策略中， 有针对性地进行治疗干预。该计划将检验EBV癌症发生在 代谢和表观遗传途径中改变EBV潜伏期和致瘤性的体细胞突变的背景，以及 这种病毒和宿主的相互依赖如何提供治疗机会。要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来解决以下问题：(1)确定EBV如何 在上皮性癌细胞中建立潜伏的致癌感染(2)确定EBV如何潜伏 感染驱动表观遗传和代谢转变，包括CpG岛甲基化的形成 表型(CIMP)促进上皮细胞肿瘤发生。(三)运用机械洞察力发展 治疗EB病毒上皮癌的新治疗策略。这3个项目主要关注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(Gewurz)。这3个科学核心支持生物信息学、药物发现和 EBV癌症支持作为研究增强剂的3个项目中的每一个。这个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 针对病毒的治疗策略和以精确为基础的医学。

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.