A novel CDC25B promoter based oncolytic adenovirus inhibited growth of orthotopic human pancreatic tumors in different preclinical models
Menée sur des lignées cellulaires et des modèles murins de cancer du pancréas, cette étude met en évidence des mécanismes par lesquels, en combinaison avec la gemcitabine, un adénovirus oncolytique (AVC25CDC) inhibe la croissance tumorale
Purpose: We decided to construct a novel oncolytic adenovirus whose replication was driven by the CDC25B promoter for its use in preclinical models of pancreatic cancer. Experimental design: We placed the essential E1A gene under control of the CDC25B promoter. Based on preliminary data we pseudotyped the adenovirus with a chimeric fiber of serotypes 5/3. We investigated the in vitro lytic effect and the in vivo therapeutic efficacy in combination with gemcitabine, on human pancreatic tumor xenografts orthotopically growing in nude mice, and in tumors growing in Syrian hamsters. We also assessed biochemical markers of hepatic toxicity and CA19.9 levels. Results: AV25CDC exhibited a strong in vitro lytic effect on pancreatic cancer cells. In vivo administration of AV25CDC combined with gemcitabine in mice harboring s.c. growing SW1990 pancreatic tumors, almost abrogated tumor growth. Nude mice harboring 15-days old orthotopic tumors, treated i.t. or systemically with AV25CDC combined with gemcitabine, exhibited 70%-80% reduction in tumor size compared to control mice that lasted for at least 60 days. Chemo-virotherapy treatment induced a return to normal levels of biochemical parameters of hepatic toxicity; these mice exhibited more than 90% reduction in CA19.9 serum levels compared to control. Chemo-virotherapy efficacy was confirmed in mice harboring Mia PaCa-2 tumors and in Syrian hamster harboring HaP-T1 tumors. We observed that viral treatment disrupted tumor architecture and induced an increase in MMP-9 activity that might facilitate gemcitabine penetrability. Conclusions: These data demonstrates that AV25CDC is an effective oncolytic agent candidate for pancreatic cancer chemo-virotherapy combination.