cancers Review The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer Domenico Ribatti 1, * , Antonio Giovanni Solimando 2,3 and Francesco Pezzella 4   Citation: Ribatti, D.; Solimando, A.G.; Pezzella, F. The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer. Cancers 2021, 13, 3433. https:// doi.org/10.3390/cancers13143433 Academic Editor: Dietmar Abraham Received: 30 May 2021 Accepted: 6 July 2021 Published: 8 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy 2 Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, 70124 Bari, Italy; antonio.solimando@uniba.it 3 IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy 4 Nuffield Division of Laboratory Science, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX39DU, UK; francesco.pezzella@ndcls.ox.ac.uk * Correspondence: domenico.ribatti@uniba.it; Tel.: +39-080-547832 Simple Summary: Several anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents. Angiogenesis inhibitors cause drug resistance, metastasis formation, and reduced delivery of chemotherapeutic agents, as a consequence of decrease of tumor vasculature. The endothelial cells as gatekeepers inspired a revisited interpretation of the vascular function in several malignancies. Abstract: Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co- option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check- point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key. Keywords: angiogenesis; anti-angiogenesis; bevacizumab; drug resistance; VEGF 1. Introduction Several anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents, and anti-angiogenic therapy is essentially an anti-vascular endothelial growth factor (VEGF) or anti-VEGF-receptor (VEGFR) ther- apy [1]. The first anti-angiogenic drug, bevacizumab (Avastin), a humanized anti-VEGF-A monoclonal antibody, was approved for the treatment of previously untreated metastatic colorectal cancers in combination with chemotherapy [2]. Ranibizumab is a humanized antibody based on a single antigen-binding site (Fab) derived from bevacizumab, but with a higher VEGF-A binding activity. Tyrosine kinase inhibitors are additional anti-angiogenic drugs, which interfere with VEGFR-1, VEGFR-2, platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFRs), and Tie2 signaling [3]. VEGF-trap protein aflibercept, obtained by fusion of VEGF binding domain of VEGFR-1 and R-2, which acts as a ‘VEGF ligand trap’, has been approved for the treatment of metastatic colorectal cancer [4]. Cancers 2021, 13, 3433. https://doi.org/10.3390/cancers13143433 https://www.mdpi.com/journal/cancers