Novel VEGF signalling inhibitors: how helpful are biomarkers in their early development?
BACKGROUND
The development of vascular endothelial growth factor (VEGF) inhibitors of tumour angiogenesis can only be described as prolific. It is therefore interesting to speculate which will reach the clinic. Of course, the most effective agents will succeed, but how is effectiveness measured? When presented with a summary of competitive compounds, it can be difficult to discriminate between their potency on target, toxicity and response rates.


OBJECTIVE
A comparison was undertaken between new small-molecule tyrosine kinase inhibitors with vascular endothelial growth factor receptor as one of their targets. Factors considered included mode of action (targets), toxicity and usefulness of biomarker data.


METHODS
We carried out a systematic review using PubMed, MEDLINE and American Society of Clinical Oncologist (ASCO) databases for articles (including abstracts) presented in 2007 - 2009. Search terms included 'angiogenesis inhibitors', 'tyrosine kinase inhibitors', 'VEGF' and 'biomarkers'. Nine compounds were selected for detailed comparison.


CONCLUSIONS
The toxicity profiles of the compounds were similar. Many exposure biomarkers have been identified that have informed the dose and scheduling of these compounds in clinical trials. Progress has also been made in identifying potential efficacy and predictive biomarkers for these new agents; however, these are yet to be validated.
Wood
Joanna
J
University of Leicester, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
Scott
Edwina
E
Thomas
Anne L
AL
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor