Renal Cancer a Model for Development of Antiangiogenic Compounds

Armand Jean-Pierre

Medical Director IGR&D, Institut Gustave Roussy,38 rue Camille Desmoulins, Villejuif,94805, France

There has been an increase in the incidence of all stages of kidney cancer, the cause for which is unknown. High-dose bolus interleukin-2 and interferon were the only approved therapy in Europe for patients with advanced kidney cancer. However they benefit only a small subset of patients with advanced kidney cancer. Clear Renal Cancer Cell is part of the inherited forms of Renal Carcinoma in the Von Hippel Lindau syndrome (VHL) and the VHL pathway can be targeted by HIF (Hypoxia Inducible Factor)and VEGF (Vascular Endothelial Growth Factor). Several investigational strategies have shown initial encouraging results. These results are based on new knowledge on angiogenesis, and signal transduction pathways important in malignant transformation. Antiangiogenic strategies include therapies targeted VEGF, its receptor, or the downstream signaling of the VEGF receptor. As more is understood about molecular pathways involved in the initiation and maintenance of the malignant phenotype potential, new targets for therapeutic intervention are identified. Agents involved in the inhibition of several of these pathways are being evaluated and confirmed in advanced kidney cancer, monoclonal antibodies, and tyrosine kinase inhibitor are active drugs. RhuMab VEGF targeting VEGF is well tolerated with significant activity (21 % OR – 45 % SD).Different tyrosine kinase inhibitors (TKI)have demonstrated activity : Bay 439006 initially described as a Raf kinase inhibitor is clearly acting as an anti VEGF (15 % OR)A positive randomized trial presented in 2005 has recognized it ad the first TKI for kidney cancer,this drug was the first to be registered in US and europe in second line . . Ag 013736 targeting VEGF and PDGF act as a simple bi targeted compound but SU 11248, a multi targeted compound (VEGF, PDGF, c-kit, FgFR), is the first of a long family of TKI (33 % PR – 37 % SD) which is probably the more potent drug presently known in kidney cancer.The drug has been registered in 2 nd line too on phase 2 data In US and in Europe .Asco 2006 has shown its critical role in first line ,where it clearly improves time to progression . PTK/ZK active in colorectal, belongs to the same family (OR 10 % - SD 50 %) .M tor inhibitors act indirectly through angiogenesis,after a long development their role has been established at ASCO 2006 ,in 1st line ,poor risk kidney cancer where it improves survival.

By the end 2006 the field of kidney cancer treatment will be totally modify by new drugs, which probably will not cure the disease but will be much more potent than the old generation of cytokines.Those classical cytokines used for 20 years and recognized as as active in kidney as progesterone in randomized trial ,should disappear from the arnementarium of the oncourologist. The optimization of the combination should explore the addition of monoclonals,to TKI with the same target or mtor inhibitors (mamouths and foxes!) . the angiogenic target model of renal cancer will be certainly be validated in other cancers and non tumoral diseases.