Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models

// Valeria Cicatiello 1, 2, * , Ivana Apicella 1, * , Laura Tudisco 1, * , Valeria Tarallo 1 , Luigi Formisano 3 , Annamaria Sandomenico 4 , Younghee Kim 5 , Ana Bastos-Carvalho 5 , Augusto Orlandi 6 , Jayakrishna Ambati 5 , Menotti Ruvo 4 , Roberto Bianco 3 , Sandro De Falco 1, 7 1 Angiogenesis Lab, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” – CNR, Naples, Italy 2 Bio-Ker, MultiMedica Group, Napoli, Italy 3 Medical Oncology, Department of Clinic Medicine and Surgery, University of Naples “Federico II”, Italy 4 Institute of Biostructures and Bioimaging – CNR and CIRPeB, University of Naples “Federico II”, Italy 5 Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, KY, USA 6 Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy 7 IRCCS MultiMedica, Milan, Italy * These authors have contributed equally to this work Correspondence to: Sandro De Falco, e-mail: sandro.defalco@igb.cnr.it Keywords: colorectal cancer, VEGFR1, angiogenesis, metastasis, choroid neovascularization Received: January 21, 2015      Accepted: February 14, 2015      Published: March 25, 2015 ABSTRACT To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 ( i nhibitor of V EGF R1 ), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo , determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro , by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.