Integrin α5β1 as a novel therapeutic target in renal cancer

Anti-angiogenics have shown efficacy in the treatment of renal cancer. Most current therapies target the VEGF pathway. In this chapter, we discuss the role of integrins, specifically α5β1, in angiogenesis. The integrin α5β1 is up-regulated on proliferating endothelial cells. The monoclonal antibody volocixi-mab is a potent, high-affinity inhibitor of α5β1. Inhibition of α5β1 function by volociximab results in the apoptosis of proliferating, but not resting, endothelial cells in vitro. Inhibitory activity of volociximab appears to be independent of the growth factor milieu, suggesting a potential role for this agent under pathological conditions where multiple growth factors are present. Additionally, in pre-clinical models of angiogenesis such as the cynomolgus choroidal neovascularization model, volociximab is effective at inhibiting lesion development. An assessment of the expression of α5β1 by immunohistochemistry in annotated samples of renal cancer suggest a relationship between α5β1 expression and clinical grade of the tumour. The analysis shows that the expression of this integrin was very high in the tumour vasculature in all the clinical grades of renal cancer tested. However, we found an increase in target expression on the tumour cells that correlated with worsening clinical grade. These results suggest an additional mechanism by which volociximab may provide clinical benefit. Volociximab may not only exert an anti-angiogenic effect but may also have a direct inhibitory effect on the tumour cells. A phase 1 clinical trial with volociximab has been completed in patients having a variety of tumour types. The results show that the antibody is well tolerated at doses up to 15 mg/kg weekly. No drug-related adverse events were noted, and the best clinical response seen so far is stable disease. Volociximab is currently undergoing further clinical testing, and is being assessed in pilot open label trials, in indications including renal cancer.