Potent and long-term antiangiogenic efficacy mediated by FP3-expressing oncolytic adenovirus

Abstract

Various ways to inhibit vascular endothelial growth factor (VEGF), a key facilitator in tumor angiogenesis, are being developed to treat cancer. The soluble VEGF decoy receptor (FP3), due to its high affinity to VEGF, is a highly effective and promising strategy to disrupt VEGF signaling pathway. Despite potential advantage and potent therapeutic efficacy, its employment has been limited by very poor in vivo pharmacokinetic properties. To address this challenge, we designed a novel oncolytic adenovirus (Ad) expressing FP3 (RdB/FP3). To demonstrate the VEGF-specific nature of RdB/FP3, replication-incompetent Ad expressing FP3 (dE1/FP3) was also generated. dE1/FP3 was highly effective in reducing VEGF expression and functionally elicited an antiangiogeneic effect. Furthermore, RdB/FP3 exhibited a potent antitumor effect compared with RdB or recombinant FP3. Consistent with these data, RdB/FP3 was shown to greatly decrease VEGF expression level and vessel density and increase apoptosis in both tumor endothelial and tumor cells, verifying potent suppressive effects of RdB/FP3 on VEGF-mediated tumor angiogenesis in vivo. Importantly, the therapeutic mechanism of antitumor effect mediated by RdB/FP3 is associated with prolonged VEGF silencing efficacy and enhanced oncolysis via cancer cell-specific replication of oncolytic Ad. Taken together, RdB/FP3 provides a new promising therapeutic approach in the treatment of cancer and angiogenesis-related diseases. What's new? The soluble VEGF decoy receptor, FP3 is a highly promising candidate to inhibit tumor angiogenesis. However, it has limited therapeutic efficacy in cancer patients and may elicit toxic side effects. To address this challenge, here the authors designed a novel cancer cell-specific oncolytic adenovirus (Ad) expressing FP3. They report for the first time that the FP3-harboring oncolytic Ad mediates an efficient and long-term antiangiogenic effect and strong antitumor effect in cancer-bearing hosts. The mechanisms of action combine sustained VEGF silencing efficacy and enhanced cancer cell-specific killing. The newly designed system thus provides a novel promising therapeutic approach in the treatment of cancer.