Brivanib, A Novel Dual VEGF-R2/bFGF-R Inhibitor

The process of neo-vascularisation from pre- existing blood vessels (angiogenesis) plays a critical role in both tumour growth and dissemination in multiple cancer types. Tumour angiogenesis is an attractive target for cancer treatment, and the VEGF/VEGF-R and FGF/FGF-R systems have been identified as key factors for neo-angiogenesis. Several active compounds have been developed so far and some of them are already widely used in clinical protocols. However, currently, only very few drugs have been shown to act synergistically with VEGF. Brivanib (BMS-582664) is a novel, orally available and selective receptor tyrosine kinase inhibitor that targets the key angiogenesis receptors VEGF-R2 and FGF-R1 and -2. The drug is currently under clinical evaluation and published data as well as data on biomarker studies with brivanib are reviewed and discussed. Angiogenesis is a fundamental mechanism in biology that describes the multistep process of new blood vessel formation from existing vasculature (1). The role of angiogenesis in normal biology and pathology is now firmly established. Angiogenesis occurs during normal tissue turnover and organogenesis, including vertebrate embryonic development, menstruation and wound repair (2, 3). Conversely, aberrant angiogenesis may contribute to the pathogenesis of a variety of both non-neoplastic (e.g. diabetic retinopathy) and neoplastic disorders. In cancer, early angiogenesis facilitates tumour cell growth through the delivery of nutrients and the removal of metabolic waste products from the tumour environment. Initially, in the course of tumour growth and expansion, tumour cells surround the microvasculature, and the resulting capillary 'cuff' facilitates their growth. Subsequently, an 'angiogenic switch', characterized by the expression of multiple pro- angiogenic factors (4), is thought to push cells out of a state of relative dormancy and into one characterised by the invasive phenotype, a hallmark of cancer pathogenesis. Among the many contributors to this process is the vascular endothelial growth factor (VEGF) family of ligands and receptors (Tables I and II). Since tumour angiogenesis is an attractive target for cancer treatment, several active compounds have been developed so far and some of them are already widely used in clinical protocols. Amongst them brivanib (a novel VEGF- R2 and FGF-R1 and -2 inhibitor) is currently under clinical evaluation and therefore it was the objective of this paper to review and discuss the potential of this new compound in treatment strategies for cancer.