Targeting EBV-associated gastric cancer by lytic induction therapy with nanatinostat

Latent Epstein-Barr virus (EBV) Infection is associated with multiple lymphoid and epithelial cancers in humans. Targeting EBV through lytic induction therapy represents a potential strategy for treating virus-associated malignancies, such as EBV-associated gastric Cancer (EBVaGC). Despite its classification as a distinct gastric Cancer subtype, precision therapeutic strategies for EBVaGC remain vastly underexplored. In a recent clinical study, the combination of an orally administered histone deacetylase (HDAC) inhibitor, nanatinostat (NSTAT) with valganciclovir (VGCV), showed promise as a lytic induction therapy for EBV-positive lymphoma. In this study, we evaluated the activity of NSTAT to induce EBV lytic reactivation and the therapeutic efficacy of NSTAT-based lytic induction therapy in two representative EBVaGC cell lines in vitro and in vivo. NSTAT efficiently induced the expression of EBV immediate-early, early and late genes in EBVaGC cells. In addition, NSTAT treatment also promoted global histone acetylation and suppressed c-Myc and BCL2 expression, leading to cell cycle arrest and cell death in the EBVaGC tumor cells. Importantly, this study demonstrated the potent antitumor efficacy and safety of combined NSTAT and ganciclovir (GCV) treatment in both in vitro and in vivo preclinical EBVaGC models.