LAUSR

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.