the platelet derived growth factor receptor beta (not shown). VEGF is one of the many target genes of hypoxia inducible factor (Hif) pathway, the master regulator of oxygen homeostasis which is constitutively active in renal cell carcinoma. In the normal Hif pathway, under normoxic conditions the Hif proteins are subject to hydroxylation by prolyl and asparagyl hydroxylases whose own enzymatic activities are oxygen dependent. The modified prolines are recognized by Vhl which then targets Hif for proteosomal degradation. When the levels of oxygen are low, Hif is not modified, translocates to the nucleus where it forms heterodimers with the beta partner to regulate the expression of target genes. Targets include genes involved in glucose and energy homeostasis, erythropoiesis and angiogenesis, among others. Vhl harbors many germline and somatic mutations; most result in loss of function for both alleles. It is believed that specific mutations underlie distinct morbidity and mortality phenotypes. The inability to target Hif for degradation renders the pathway constitutively active regardless oxygen levels. Additional stabilization of Hif appears to be due to mutations in fumarate hydratase (Fh) and succinate dehydrogenase (Sdhb and Sdhd of Sdh complex) enzymes of the citric acid cycle and in the case of Sdh of the electron transport chain as well where it functions as complex II. Either Fh or Sdh mutations affect the necessary modification of Hif under normoxic condition, creating a pseudohypoxic environment that promotes Hif activity even when Vhl might be wild type. Axitinib is one of a number of TKI used in the treatment of renal cell carcinoma; its overall pharmacokinetics are known, but the molecular details are not well characterized. The drug is a substrate for several phase I biotransformation and a phase II conjugating enzyme as well as a few transporters Non-clinical studies have shown that axitinib prevents VEGF-mediated endothelial cell adhesion and autophosphorylation of VEGF receptors, phosphorylation events involving Erk1/2 and Akt kinases downstream of VEGF receptors with concomitant reduction in vascular angiogenesis and tumor proliferation and increase in tumor apoptosis. There are several side effects associated with axitinib such as GI disturbances, nausea, fatigue and hypertension; GI and skin disturbances appear to be common among the TKI inhibitors used for the treatment of renal cell carcinoma....(less)