Anti-angiogenic drug discovery: lessons from the past and thoughts for the future.
BACKGROUND
Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects.


METHODS
This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti-VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment.


CONCLUSIONS
Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal.
University of Sheffield, School of Medicine and Biomedical Sciences, CR-UK/YCR Sheffield Cancer Research Centre, Academic Unit of Surgical Oncology, Microcirculation Research Group, Beech Hill Road, Sheffield, South Yorkshire, S10 2RX, UK.
Jessie M
JM
Wu
Carolyn A
CA
Staton
D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A