Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma
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Cheng-Lung Hsu1, Yung-Chia Kuo1, Yenlin Huang2, Yin-Cheng Huang3, Kar-Wai Lui4, Kai-Ping Chang5, Tung-Liang Lin1, Hsien-Chi Fan1, An-Chi Lin1, Chia-Hsun Hsieh1, Li-Yu Lee2, Hung-Ming Wang1, Hsin-Pai Li6, Yu-Sun Chang6
1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC
2Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC
3Division of Neurologic Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC
4Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC
5Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC
6Department of Cell and Molecular Biology, Chang Gung University, Taoyuan 333, Taiwan, ROC
Cheng-Lung Hsu, e-mail: email@example.com
Keywords: NPC, PDX, EBV, target therapy, viral lytic therapy
Received: July 09, 2015 Accepted: September 11, 2015 Published: September 24, 2015
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.
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