Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors

Abstract

The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF) ligands that is expressed in endothelial, myelomonocytic and tumor cells. VEGF-B and PlGF exclusively bind to VEGFR-1, whereas VEGF-A also binds to VEGFR-2. At variance with VEGFR-2, VEGFR-1 does not play a relevant role in physiological angiogenesis in the adult, while it is important in tumor-associated angiogenesis. VEGFR-1 and PlGF are expressed in a variety of tumors, promote invasiveness and contribute to resistance to anti-VEGF-A therapy. The currently approved antiangiogenic therapies for the treatment of a variety of solid tumors hamper VEGF-A signaling mediated by both VEGFR-2 and VEGFR-1 [i.e., the monoclonal antibody (mAb) anti-VEGF-A bevacizumab, the chimeric molecule aflibercept and several small molecule tyrosine kinase inhibitors] or exclusively by VEGFR-2 (i.e., the mAb anti-VEGFR-2 ramucirumab). However, molecules that interfere with VEGF-A/VEGFR-2 signaling determine severe adverse effects due to inhibition of physiological angiogenesis and their efficacy is hampered by tumor infiltration of protumoral myeloid cells. Blockade of VEGFR-1 may exert anti-tumor activity by multiple mechanisms: a) inhibition of tumor-associated angiogenesis; b) reduction of myeloid progenitor mobilization and tumor infiltration by VEGFR-1 expressing M2 macrophages, which contribute to tumor progression and spreading; c) inhibition of invasiveness, vasculogenic mimicry and survival of VEGFR-1 positive tumor cells. As a consequence of these properties, molecules targeting VEGFR-1 are expected to produce less adverse effects and to counteract resistance towards anti-VEGF-A therapies. More interestingly, selective VEGFR-1 inhibition might enhance the efficacy of immunotherapy with immune checkpoint inhibitors. In this review, we will examine the experimental evidence available so far that supports targeting VEGFR-1 signal transduction pathway for cancer treatment by competitive inhibitors that prevent growth factor interaction with the receptor and non-competitive inhibitors that hamper receptor activation without affecting ligand binding.

Keywords: Angiogenesis; Axitinib: (PubMED CID: 6450551); Bevacizumab: (PubMED CID: 24801580); Cabozantinib: (PubMED CID: 25102847); Immune checkpoint inhibitors; Lenvatinib: (PubMED CID: 9823820); Melanoma; Nintedanib: (PubMED CID: 9809715); Non-small cell lung cancer; Pazopanib: (PubMED CID: 10113978); Regorafenib: (PubMED CID: 11167602); Sorafenib: (PubMED CID: 216239); Sunitinib: (PubMed CID: 5329102); Tumor-associated; Vandetanib: (PubMed CID: 3081361); Vascular endothelial growth factor receptor-1; macrophages.