Iron Chelators and HDAC Inhibitors Are Potent Inducers of Epstein-Barr Virus Lytic Cycle in Stomach Adenocarcinoma

Abstract Epstein-Barr Virus (EBV) is a complex oncogenic γ-herpesvirus that infects around 90% of the global adult human population. Upon primary infection, EBV typically persists asymptomatically in form of a latent infection. However, under certain circumstances the virus can malignantly transform lymphocytes and epithelial cells leading to cancers such as Diffuse Large B Cell Lymphoma (DLBCL) and Stomach Adenocarcinoma (STAD) respectively. Unfortunately, it is difficult to target latent EBV using the current immuno-therapeutic strategies, specifically due to reduced antigen expression. Cytolytic Virus Activation (CLVA) therapy is an approach that can specifically target and kill tumor cells that harbor EBV in a lytic state. The switch from latent to lytic phase can be mediated by a plethora of chemical compounds or lytic inducers. Recently, in our lab, we have developed an intuitive in-silico drug prediction approach to rapidly screen and identify FDA-approved or clinically available compounds that can be repurposed to induce lytic cycle in different EBV+ tumors. Using this strategy, we identified a range of HDACi and Iron chelators as inducers of lytic cycle in EBV+ epithelial cancers. Interestingly, these drugs also significantly induced the expression of Programmed Death Ligand-1 (PD-L1) protein, a major target of Immune checkpoint blockade (ICB) therapy. This led us to hypothesize that by utilizing such an in-silico drug prediction approach, we can identify cancer specific drugs that are potent inducers of EBV lytic cycle. To better understand the underlying mechanisms, we are now investigating the effect of these cytolytic compounds in vivo using xenograft mouse models. Supported by SIRG Graduate Research Assistantship Award PCCR-SIRG-FY2022-01 (P30CA023168) from Purdue University