FIBER MODIFICATION AUGMENTS ANTITUMOR EFFECT OF CONDITIONALLY REPLICATIVE ADENOVIRUS UPON SYSTEMIC ADMINISTRATION IN ORTHOTOPIC PANCREATIC CANCER MODEL

Abstract

Background: Pancreatic cancer, which is most often unresectable upon diagnosis, demands the development of novel therapeutic modalities for systemic usage. While conditionally replicative adenovirus (CRAd) is promising candidate, poor expression of adenoviral primary receptor impedes getting requisite tumor transduction in this tumor context. We have reported that adenoviral fiber modifications (RGD modification and Ad5/3 modification) enhance the CRAd efficiency upon intratumoral injection. In this study, we analyzed the fiber modified CRAds upon systemic vector administration in orthotopic pancreatic cancer xenograft model. Method: An Hs766T subcutaneous xenograft was established in a nude mouse first. Then, the small pieces (1mm3) made from this parental tumor were transplanted into pancreatic bed of other nude mice to establish the orthotopic tumor. Luciferase expression vectors with fiber modifications were used for comparing tumor transduction efficiency. The cyclooxygenase (COX)-2 promoter-based CRAd and its fiber modified versions were used for analyzing CRAd anti-tumor effect. The viruses were injected from tail vein 3 days after tumor transplantation. Mice are sacrificed 2 days and 28 days after vector administration for evaluating tumor transduction and the anti-tumor effect. Results: As for in vivo tumor transduction, Ad5/3 modified vector showed significantly (8 times) higher transduction compared to the background. This tumor transduction enhancement was also observed in pancreatic cancer subcutaneous xenografts upon systemic vector administration. When CRAds were injected systemically to assess the therapeutic effect in the mice with orthotopic tumors, the volume of the tumor treated with 5/3 CRAd COX-2 was significantly lower than that with non-replicative control virus, and comparable to non-selectively replicating wild type Ad. In the harvested tumors, the viral copy number of the 5/3 COX-2 CRAd was significantly high, even in comparison with non-selective wild type Ad. Conclusion: Ad5/3 modification enhanced the therapeutic effect of systemically administered CRAd. This suggests the benefits of adenoviral tropism modification as a way to achieve therapeutic effect in clinically relevant settings.