Mechanisms of resistance to antiangiogenesis therapy.

Angiogenesis, the formation of new blood vessels from existing vasculature, plays an essential role in tumour growth, invasion and metastasis. Vascular endothelial growth factor (VEGF) is one of the key factors responsible for its regulation. High expression of VEGF has been observed in many cancers, and is associated with worse survival. When antiangiogenic agents are used alone they typically initially cause reduction in blood flow or vascular permeability, in many types of cancer. In some cases tumour regression occurs, mainly in renal cancer. In combination with chemotherapy, progression-free survival is often prolonged, but overall survival is not. Many tumours fail to respond initially - de novo resistance. Others develop resistance over time, with progression after a few months of treatment. The mechanisms of resistance are not well understood. The theoretical benefits of VEGF inhibitors are more likely to be realised by understanding these mechanisms and modifying therapy accordingly. This article reviews current knowledge on resistance mechanisms and the therapeutic implications.