Cytolytic virus activation therapy and treatment monitoring for Epstein‐Barr virus associated nasopharyngeal carcinoma in a mouse tumor model

• Published in: Journal of medical virology Vol. 89; no. 12; pp. 2207 - 2216
• Main Authors: Novalić, Zlata, Verkuijlen, Sandra A. W. M., Verlaan, Mariska, Eersels, Jos L. H., de Greeuw, Inge, Molthoff, Carla F. M., Middeldorp, Jaap M., Greijer, Astrid E.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2017; John Wiley and Sons Inc
• Subjects: Activation; Animals; Antiviral Agents - blood; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Carcinoma - drug therapy; Carcinoma - virology; cytolytic virus activation therapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA, Viral - genetics; EBV DNA load; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - drug therapy; Epstein-Barr Virus Infections - virology; Ganciclovir; Ganciclovir - administration & dosage; Ganciclovir - blood; Ganciclovir - therapeutic use; Gemcitabine; Herpesvirus 4, Human - drug effects; Herpesvirus 4, Human - physiology; Humans; In vivo methods and tests; Kinases; Kinetics; Mice; Mice, Nude; Monitoring; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - virology; PET‐scan; Positron emission; Proteins; Reaction kinetics; targeted cancer therapy; Therapy; Throat cancer; Tomography; treatment monitoring; Treatment Outcome; Tumor cells; Tumor Cells, Cultured; Tumors; Valproic acid; Valproic Acid - pharmacology; Valproic Acid - therapeutic use; Viral Load - methods; Virology; Virus Activation; Viruses; targeted cancer therapy; nasopharyngeal carcinoma; PET-scan; Epstein-Barr virus; cytolytic virus activation therapy; treatment monitoring; EBV DNA load
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.24870

Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein‐Barr virus (EBV). Expression of viral proteins in the tumor cells is highly restricted. EBV reactivation by CytoLytic Virus Activation (CLVA) therapy triggers de novo expression of early viral kinases (PK and TK) and uses antiviral treatment to kill activated cells. The mechanism of tumor elimination by CLVA was analyzed in NPC mouse model using C666.1 cells. Valproic acid (VPA) was combined with gemcitabine (GCb) to stimulate EBV reactivation, followed by antiviral treatment with ganciclovir (GCV). A single cycle of CLVA treatment resulted in specific tumor cell killing as indicated by reduced tumor volume, loss of EBV‐positive cells in situ, and paralleled by decreased EBV DNA levels in circulation, which was more pronounced than treatment with GCb alone. In vivo reactivation was confirmed by presence of lytic gene transcripts and proteins in tumors 6 days after GCb/VPA treatment. Virus reactivation was visualized by [124I]‐FIAU accumulation in tumors using PET‐scan. This studied showed that CLVA therapy is a potent EBV‐specific targeting approach for killing tumor cells. The [124I]‐FIAU appears valuable as PET tracer for studies on CLVA drug dosage and kinetics in vivo, and may find clinical application in treatment monitoring.