Electrotransfer of Antiangiogenic shRNA against Endoglin for Effective Cancer Treatment

Abstract

Endoglin (CD105) is involved in activation and proliferation of tumor endothelial cells. Its pronounced role was recently described in tumors that became resistant to standard anti-VEGF(R) antiangiogenic therapies. In our ongoing studies, the feasibility of targeting endoglin with gene therapy using RNA interference technology was elaborated at the molecular, cellular and organism level. We prepared plasmids encoding shRNA against endoglin under the control of different promoters and evaluated their therapeutic potential in electrogene therapy of different cancers. In TS/A adenocarcinoma tumors, which do not express endoglin, anti-endoglin gene therapy resulted in vascular targeted effect that was more pronounced when plasmid encoding shRNA was used, than when siRNA molecules against endoglin were employed. Furthermore, the plasmid encoding shRNA against endoglin under the control of endothelial cell specific promoter was equally effective as the plasmid with the strong constitutive promoter. In addition, in melanoma tumors, which express endoglin, besides vascular targeted effect, a significant antitumor and anti-metastatic effects were obtained. Collectively, our results demonstrate that endoglin is a suitable target for vascular targeted gene therapy approach and promote further studies with clinically suitable and safe plasmids devoid of antibiotic resistance gene and under the control of tissue specific promoters.