Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model

We have examined whether Ad.sT beta RFc and TAd.sT beta RFc, two oncolytic viruses expressing soluble transforming growth factor-beta receptor II fused with human Fc (sTGF beta RIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sT beta RFc and TAd.sT beta RFc produced sTGF beta RIIFc and viral replication; sTGF beta RIIFc caused inhibition of TGF-beta-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sT beta RFc, an E1(-) adenovirus, produced sTGF beta RIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5 x 10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sT beta RFc, TAd.sT beta RFc, and Ad(E1-).sT beta RFc caused significant inhibition of tumor growth; however, Ad.sT beta RFc was the most effective among all the vectors. Only Ad.sT beta RFc and TAd.sT beta RFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sT beta RFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sT beta RFc and TAd.sT beta RFc can be developed as potential new therapies for prostate cancer bone metastasis.