Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation.

Hyun Gyu Lee,Richard F Ambinder,Jae Myun Lee,Pil-Gu Park,Seung Myung Dong,S Diane Hayward,Eun Jung Kim,Jeon Han Park,Tae Hyun Choi,Hyemi Kim,Curtis R Chong,Jun O Liu,Jianmeng Chen,Hyunki Kim

doi:10.18632/oncotarget.5041

Abstract

The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs.

Highlights

Epstein-Barr virus (EBV) is a double-stranded DNA human gamma herpes virus that establishes a persistent infection in over 90% of individuals
Treatment of the EBV-associated gastric carcinomas (EBVaGCs) cell line SNU-719 and the EBV-negative gastric cancer (EBVnGC) cell line MKN-74 with gemcitabine as scheduled in Figure 1A revealed that the EBV immediate early (IE) lytic protein Zta was induced in SNU-719 cells even at a low dose (5 ng/ml; Figure 1B)
Most Zta expression was diminished by si-ataxia telangiectasia-mutated (ATM) and siTP53

Summary

Introduction

Epstein-Barr virus (EBV) is a double-stranded DNA human gamma herpes virus that establishes a persistent infection in over 90% of individuals. Most infections are self-limiting, but some cases are associated with the development of malignancies of lymphoid or epithelial origin [1]. The presence of EBV in lymphoma or leukemia is known to confer a poorer prognosis [3,4,5]; a recent retrospective study revealed that EBV positivity in gastric cancer is associated with lower mortality and provides an additional prognostic indicator [2]. Recent studies www.impactjournals.com/oncotarget based on the concept of selective destruction of tumor cells have suggested that the induction of lytic activation in EBV-associated tumors and combination treatment with the antiviral agent ganciclovir (GCV) represents a potential anti-cancer treatment modality [7,8,9,10]

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