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Powerful Anti-Tumor and Anti-Angiogenic Activity of a New Anti- Vascular Endothelial Growth Factor Receptor 1 Peptide in Colorectal Cancer Models

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Powerful Anti-Tumor and Anti-Angiogenic Activity of a New Anti- Vascular Endothelial Growth Factor Receptor 1 Peptide in Colorectal Cancer Models University of Kentucky UKnowledge Ophthalmology and Visual Science Faculty Publications Ophthalmology and Visual Science 4-30-2015 Powerful Anti-Tumor and Anti-Angiogenic Activity of a New Anti- Vascular Endothelial Growth Factor Receptor 1 Peptide in Colorectal Cancer Models Valeria Cicatiello Institute of Genetics and Biophysics, Italy Ivana Apicella Institute of Genetics and Biophysics, Italy Laura Tudisco Institute of Genetics and Biophysics, Italy Valeria Tarallo Institute of Genetics and Biophysics, Italy Luigi Formisano University of Naples, Italy Follow this and additional works at: https://uknowledge.uky.edu/ophthalmology_facpub Part of the Ophthalmology Commons See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Repository Citation Cicatiello, Valeria; Apicella, Ivana; Tudisco, Laura; Tarallo, Valeria; Formisano, Luigi; Sandomenico, Annamaria; Kim, Younghee; Bastos-Carvalho, Ana; Orlandi, Augusto; Ambati, Jayakrishna; Ruvo, Menotti; Bianco, Roberto; and De Falco, Sandro, "Powerful Anti-Tumor and Anti-Angiogenic Activity of a New Anti- Vascular Endothelial Growth Factor Receptor 1 Peptide in Colorectal Cancer Models" (2015). Ophthalmology and Visual Science Faculty Publications. 10. https://uknowledge.uky.edu/ophthalmology_facpub/10 This Article is brought to you for free and open access by the Ophthalmology and Visual Science at UKnowledge. It has been accepted for inclusion in Ophthalmology and Visual Science Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Powerful Anti-Tumor and Anti-Angiogenic Activity of a New Anti-Vascular Endothelial Growth Factor Receptor 1 Peptide in Colorectal Cancer Models Digital Object Identifier (DOI) http://dx.doi.org/10.18632/oncotarget.3384 Notes/Citation Information Published in Oncotarget, v. 6, no. 12, p. 10563-10576. Copyright @ 2008-2016 Impact Journals, LLC. All rights reserved. Licensed under a Creative Commons Attribution 3.0 License. Authors Valeria Cicatiello, Ivana Apicella, Laura Tudisco, Valeria Tarallo, Luigi Formisano, Annamaria Sandomenico, Younghee Kim, Ana Bastos-Carvalho, Augusto Orlandi, Jayakrishna Ambati, Menotti Ruvo, Roberto Bianco, and Sandro De Falco This article is available at UKnowledge: https://uknowledge.uky.edu/ophthalmology_facpub/10 www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 12 Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models Valeria Cicatiello1,2,*, Ivana Apicella1,*, Laura Tudisco1,*, Valeria Tarallo1, Luigi Formisano3, Annamaria Sandomenico4, Younghee Kim5, Ana Bastos-Carvalho5, Augusto Orlandi6, Jayakrishna Ambati5, Menotti Ruvo4, Roberto Bianco3, Sandro De Falco1,7 1Angiogenesis Lab, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” – CNR, Naples, Italy 2Bio-Ker, MultiMedica Group, Napoli, Italy 3Medical Oncology, Department of Clinic Medicine and Surgery, University of Naples “Federico II”, Italy 4Institute of Biostructures and Bioimaging – CNR and CIRPeB, University of Naples “Federico II”, Italy 5Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, KY, USA 6Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy 7IRCCS MultiMedica, Milan, Italy *These authors have contributed equally to this work Correspondence to: Sandro De Falco, e-mail: [email protected] 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 (inhibitor of VEGFR1), 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. INTRODUCTION growth factors (VEGF) and related receptors play a central role in promoting vessel formation and maturation. Indeed, The development and maintenance of functional since a decade they are the only validated targets for the vessels through angiogenesis and arteriogenesis processes anti-angiogenesis therapy in cancer and ocular neovascular in pathological conditions require the cooperation of diseases [3, 4]. After the approval by FDA of bevacizumab several growth factor families, of multiple cell types and (Avastin), a humanized monoclonal antibody (mAb) the presence of certain conditions such as hypoxia and against VEGF-A for the treatment of metastatic colorectal inflammation [1, 2]. The family of vascular endothelial carcinoma (mCRC) in combination with chemotherapy www.impactjournals.com/oncotarget 10563 Oncotarget [5], other anti-angiogenic drugs targeting members of during the epithelial–mesenchymal transition [20]. VEGF family have been developed such as aflibercept, a Furthermore, VEGFR1 activation markedly promotes recombinant fusion protein consisting of VEGF-binding pulmonary metastases through induction of matrix extracellular domains of VEGFR1 and VEGFR2 fused to metalloproteinase-9 secretion [21] and plays a crucial role the Fc portion of human IgG1, and several multitargets in the establishment of pre-metastatic niches [22]. tyrosine kinase inhibitors which inhibit also VEGF The functional role of VEGFR1 in tumor and receptors [4]. metastasis contexts was confirmed using inhibitors from Anti-angiogenic drugs have been approved to different sources. Ribozyme [23], mAb [24], peptides [25, treat different types of cancer, such as mCRC, non-small 26], or DNAzyme [27] specifically targeting VEGFR1, all cell lung carcinoma, metastatic renal cell carcinoma, inhibit tumor growth and metastasis formation. gastrointestinal stromal tumor, hepatocellular carcinoma, Here, we describe the potent anti-angiogenic, and others. However, despite the significant clinical anti-tumor, and anti-metastatic activity of a tetrameric success of anti-angiogenic therapies, alternative strategies tripeptide named iVR1 (inhibitor of VEGFR1), which are desirable to improve their therapeutic efficacy and to is able to specifically bind mouse and human VEGFR1 overcome inherent/acquired resistance and the relevant blocking receptor activation by preventing the interaction side effects [6, 7]. of the natural ligands VEGF-A, VEGF-B, PlGF and VEGF receptor 1 (VEGFR1, also known as Flt- VEGF-A/PlGF heterodimer (IC50 6–10 μM) [28]. 1) is the common receptor for the three pro-angiogenic The anti-angiogenic activity of iVR1 has been first family members VEGF-A, VEGF-B, and placental growth assessed in the choroid neovascularization (CNV) model. factor (PlGF). It is the unique receptor for VEGF-B and Then, iVR1 activity has been assayed in syngenic and PlGF, and shows higher affinity for VEGF-A compared xenograft models of colorectal cancer and compared to to VEGFR-2 (also known as KDR or Flk-1), which is that of mAbs inhibiting the two main ligands of VEGFR1, exclusively recognized by VEGF-A. VEGFR1 expression VEGF-A and PlGF. The ability of iVR1 to synergize is upregulated by hypoxia and is also expressed as with chemotherapy, as well as the anti-metastatic soluble form generated by an alternative splicing (termed properties, evaluating lung invasion by colorectal cancer sVEGFR1), which is one of the most potent physiological cells injected in the blood circulation, have been also inhibitor of angiogenesis [8]. investigated. Differently from VEGFR2 found almost exclusively in endothelial cells, VEGFR1 is expressed in several types RESULTS of cells, many of which play a fundamental role during the angiogenesis and arteriogenesis process. Endothelial cells, Anti-angiogenic in vivo activity of iVR1 bone marrow stem/precursor cells, circulating endothelial cells, stromal cells, perycites and smooth muscle cells, iVR1, previously referred as 4.23.5, has a mole- monocyte-macrophages, dendritic cells, all express cular mass of 2362.02 g/mol and is composed by the functional VEGFR1 that once activated induces mainly tripeptide H2N-D-Glu–L-Cys(Bzl)–L-Cha, where D-Glu survival, proliferation and migration pathways [9]. In is D-glutammic acid, L-Cys(Bzl) is L-cysteine-S-benzyl addition, several human cancer cells express VEGFR1 [10]. and L-Cha is L-cyclohexylalanine, engrafted on a
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