title: Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers.
abstract: Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.
authors.affiliation: Departments of Pharmacology.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Departments of Pharmacology.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Departments of Pharmacology.
authors.forename: Jiankai
authors.initials: J
authors.lastname: Liang
authors.affiliation: Departments of Pharmacology.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Departments of Pharmacology.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; and.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; and.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Departments of Pharmacology.
authors.forename: Sihan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Departments of Pharmacology.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Departments of Pharmacology.
authors.forename: Lijun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Departments of Pharmacology.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Tang
authors.affiliation: Departments of Pharmacology.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Departments of Pharmacology.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Departments of Pharmacology.
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Departments of Pharmacology.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Departments of Pharmacology.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Biochemistry, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Departments of Pharmacology.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China;
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Microbiology, Zhongshan School of Medicine and hujun@mail.sysu.edu.cn ygm@mail.sysu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Departments of Pharmacology, hujun@mail.sysu.edu.cn ygm@mail.sysu.edu.cn.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000524:Alphavirus / Q000145:classification*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000145:classification*; D034622:RNA Interference; D046888:Tissue Array Analysis; D016335:Zinc Fingers
chemical_list: D020169:Caspases
keywords: personalized medicine; translational inhibition; unfolded protein response