Mouse model for solid Epstein-Barr Virus-driven cancers

This revised R21 application responds to PAR-23-056 / Co-infections and Cancer. Epstein-Barr Virus (EBV / HHV4) is a “known oncogenic agent” as defined by this PAR and the International Agency for Research on Cancer (IARC). The overall goal of this proposal is to develop a transgenic model and novel cell culture reagents for EBV-driven tumors. EBV-associated tumors include B, T, and NK cell lymphomas as well as epithelial lineage cancers. While reasonable models for EBV B-cell lymphomas exist, no animal model exists for EBV-associated epithelial lineage cancers, such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). The majority of EBV models are immunodeficient, as the immune response to cancer can only be partially modeled in culture, organoids, or humanized mice. We hypothesize that this new approach will generate new models that address these gaps in our knowledge and that will facilitate bench-to-bedside translation of new treatments. This hope is based on our recent success in developing a transgenic mouse for a related gamma-herpesvirus. This novel approach will allow us to study the role of EBV transcription, EBV microRNAs, and EBV proteins in vivo. In contrast to many EBV lymphoma models, the new transgenic mice will be (a) fully immunocompetent and (b) carry the entire complement of the viral genome, not just a single one. Thus, they will be helpful for therapy evaluation based on small molecules or immune modulation (PD1, PDL-1 inhibitors). This proposal will also derive novel cell lines for the preliminary assessment of small molecules that target evolutionarily conserved virus-host interactions and thereby reduce animal use. Project Number: 1R21CA305318-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Dirk Dittmer | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $394,214 | Activity Code: R21 | Study Section: Viral Pathogenesis and Immunity Study Section [VPI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371824