Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers

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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.