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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)31018-31029
Number of pages12
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - 2015

Keywords

  • Ataxia telangiectasia-mutated
  • EBVaGC mouse model
  • Epstein-Barr virus-associated gastric carcinoma
  • Gemcitabine
  • P53

ASJC Scopus subject areas

  • Oncology

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