A novel oncolytic adenovirus therapeutically effective in melanoma tumor

MARIA V. LOPEZ; DIEGO VIALE; EDUARDO G. CAFFERATA; DANIELA R. MACCIO; CARBONE C; DAVID GOULD; YUTI CHERNAJOVSKY; OSVALDO L. PODHAJCER

Rosario

Congreso; SAIB; 2006

SPARC is a matricellular protein that is overexpressed in malignant and stromal components of human melanomas and SPARC promoter could be a good candidate for generating a conditional replicating oncolytic adenovirus. By using luciferase expression as a reporter gene, we selected the promoter sequence F512 (?513/+35) that showed the best ratio of activity vs. specificity. We constructed three adenoviral vectors in which the E1A gene was driven by F512. The lytic capacity of viruses was initially tested in vitro on a panel of malignant cells, melanoma (n=4), colon (n=4), breast (n=3) and cervix (n=1); and normal cells (melanocyte, colon, mesenchymal, fibroblasts and endothelial cells). We found that CRAds based on SPARC promoter seem to replicate specifically in cancer cells while preserving normal cells. Finally, nude mice harboring SB2 melanoma tumors (mean 120 mm3) were treated intratumoraly with three administrations of 1010 vp/mouse of adenoviruses. The treatment resulted in a potent antitumor effect. In 3 out of 5 mice, the tumor was completely eliminated, and one mouse showed a slight tumor growth, while in mice treated with control virus we observed no therapeutic benefit. These results indicate that CRAds based on SPARC selectively replicate in and eliminate a panel of cancer cells and subcutaneous tumors, suggesting that they might be useful as pan-oncolytic viruses.