The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer

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.

The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin

“…In cancer, pathological angiogenesis contributes to tumor development, increasing proliferation, growth, and metastasis [1,101]. Angiogenesis is maintained by the overproduction of proangiogenic factors, including growth factors, matrix proteinases, and extracellular matrix molecules [100,102]. Different approaches have already shown that eNOS-derived NO signaling in endothelial cells is a critical mechanism of vascular homeostasis, mediating angiogenesis and contributing to increased cell proliferation and migration of endothelial cells and consequently to tumor progression [103][104][105].…”

Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

“…Tumor angiogenesis is a prerequisite of neoplastic growth. Consequently, angiogenesis was identified as a target for cancer therapy decades ago [46][47][48][49][50]. One of the key regulators of tumor angiogenesis is Vascular Endothelial Growth Factor (VEGF).…”

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…The main goal of anti-angiogenic therapy is to block the growth of new blood vessels and control tumor growth. For this purpose, a great number of strategies inhibiting VEGF, its receptor VEGFR and other pro-angiogenic molecules were carried out to be used in the clinic, mainly in combination with chemotherapy [21]. However, although some improvements were observed in overall survival, the benefit of anti-angiogenesis is very limited.…”

“…Bevacizumab (Avastin) was the first drug approved for the treatment of metastatic colorectal cancer in combination with chemotherapy. Avastin is a humanized anti-VEGFA monoclonal antibody [21]. Secondly, Ranibizumab is a molecule derived from Bevacizumab but having a single antigen-binding site and a higher VEGFA binding activity [21,34].…”

“…Avastin is a humanized anti-VEGFA monoclonal antibody [21]. Secondly, Ranibizumab is a molecule derived from Bevacizumab but having a single antigen-binding site and a higher VEGFA binding activity [21,34]. Moreover, other anti-angiogenic drugs are tyrosine kinase inhibitors that block cell signaling through VEGFR-1, VEGFR-2, PDGFR (PDGF-receptor), FGFR (FGF-receptor) and other signaling pathways [34].…”