Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?

There are three US Food and Drug Administration–approved angiogenesis inhibitors for the treatment of cancer that specifically target vascular endothelial growth factor (VEGF) signaling. Bevacizumab (monoclonal antibody to VEGF) has been shown to confer a survival advantage when used in combination with cytotoxic chemotherapy in patients with colorectal cancer and non– small-cell lung cancer. 1,2 Sorafenib and sunitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of the VEGF receptor (VEGFR) among other tyrosine kinase targets. Sorafenib has been shown to increase progression-free survival in patients with renal cell carcinoma. 3 Sunitinib has been shown to increase progressionfree survival in patients with renal cell carcinoma and GI stromal tumors. 4-6 A plethora of new small-molecule tyrosine kinase inhibitors are in preclinical development and early-phase clinical trials that target VEGFR with varying degrees of specificity, including AZD2171, which is the subject of a published report by Drevs et al