Vascular endothelial growth factor receptors and the therapeutic targeting of angiogenesis in cancer: where do we go from here?

Abstract

Vascular Endothelial Growth Factor receptors (VEGFRs), the interactions with their ligands and the subsequent signalling pathways are known to play a vital role in tumour angiogenesis. Initial clinical trials of VEGFR inhibitors were disappointing but over the past decade some therapies have been successfully brought to market. At present, VEGFR inhibitors appear to be most promising as adjuvants to conventional chemotherapy. However, several interacting signalling molecules and downstream pathways have recently been shown to interact with VEGFR signalling and provide promising novel targets, such as the platelet-derived growth factor (PDGF), epithelial growth factor (EGF), human epithelial receptor-2, (HER-2) Tie-2 and oestrogen receptors. Elucidation of this web of signalling pathways may identify new therapeutic strategies which may be used in combination with VEGFR inhibitors to augment the efficacy of anti-angiogenic cancer treatments. This review assesses the role of modulating VEGFR activity in cancer and systematically examines current evidence and trials in this area.

SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

“…VEGF ligands, of which there are four known isoforms (A-D), are released in response to ischemia and mediate their angiogenic effects by binding to specific VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3), leading to receptor dimerization and subsequent intracellular signal transduction via tyrosine kinases [117, 118]. The majority of VEGF-based radiotracers have been evaluated in the context of tumor angiogenesis imaging.…”

Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial

“…3 VEGFR-2 is highly expressed on tumor vasculature as well as on certain tumor cells. 4 Beyond expression levels, the modulation of tumor growth with anti-VEGF-A and VEGFR-2 antibodies (bevacizumab, civaflibercept, ramucirumab) and small-molecule VEGFR-2 inhibitors in cancer patients has added to the validation of VEGFR-2 as a therapeutic target in several cancer indications. 5,6 VXM01 is an orally available T-cell vaccine, based on live, attenuated S. Typhi Ty21a carrying a eukaryotic expression plasmid, which encodes VEGFR2.…”

Walking the Line: A Fibronectin Fiber-Guided Assay to Probe Early Steps of (Lymph)angiogenesis

“…The growth of new blood and lymphatic vessels from the pre-existing vasculature–angiogenesis and lymphangiogenesis respectively–serves essential functions in normal and pathological conditions, such as embryonic development, wound healing, cancer metastasis and inflammation [ 1 – 3 ]. Vascular Endothelial Growth Factors (VEGFs), acting via three tyrosine kinase receptors VEGFR1, VEGFR2 and VEGFR3, are the major regulators of (lymph)angiogenesis and VEGF signaling has been at the center of many therapeutic approaches targeting (lymph)angiogenesis[ 4 , 5 ]. While VEGF-A is considered to be the major angiogenic factor [ 6 ] and VEGF-C the lymphangiogenic one [ 7 ], there are studies showing VEGF-A inducing lymphangiogenesis [ 8 – 11 ] and conversely, VEGF-C promoting angiogenesis, [ 12 – 14 ], supporting a more complicated picture, with both growth factors involved in regulating different aspects of both angio- and lymphangiogenesis.…”