title: Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Yung-Chia
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Yenlin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Neurologic Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Yin-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Kar-Wai
authors.initials: KW
authors.lastname: Lui
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Chang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Lin
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Hsien-Chi
authors.initials: HC
authors.lastname: Fan
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Lin
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Chia-Hsun
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Department of Cell and Molecular Biology, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Hsin-Pai
authors.initials: HP
authors.lastname: Li
authors.affiliation: Department of Cell and Molecular Biology, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D002277:Carcinoma; D049109:Cell Proliferation; D004279:DNA, Viral / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D050130:Oncolytic Virotherapy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D004279:DNA, Viral; D012333:RNA, Messenger; D003841:Deoxycytidine; D014635:Valproic Acid; D015774:Ganciclovir; D000093542:Gemcitabine
keywords: EBV; NPC; PDX; target therapy; viral lytic therapy