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

Abstract

// Hyun Gyu Lee 1, * , Hyemi Kim 1, 2, * , Eun Jung Kim 3 , Pil-Gu Park 1 , Seung Myung Dong 4 , Tae Hyun Choi 3 , Hyunki Kim 5 , Curtis R. Chong 6, 7 , Jun O. Liu 8, 9 , Jianmeng Chen 9 , Richard F. Ambinder 9 , S. Diane Hayward 9 , Jeon Han Park 1 , Jae Myun Lee 1, 2 1 Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Radiopharmaceutical Research Team, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea 4 Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea 5 Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea 6 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA, USA 7 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, MA, USA 8 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA 9 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA * These authors have contributed equally to this work Correspondence to: Jae Myun Lee, e-mail: [e-mail] Keywords: Epstein-Barr virus-associated gastric carcinoma, gemcitabine, ataxia telangiectasia-mutated, p53, EBVaGC mouse model Received: March 16, 2015      Accepted: August 24, 2015      Published: September 04, 2015 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 [ 125 I] 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.