Anti-angiogenic targets in the treatment of advanced renal cell carcinoma.
Drugs that target the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) pathways have revolutionized the treatment of patients with metastatic renal cell cancer (RCC). Patients with clear cell RCC often have mutations or silencing of the von Hippel Lindau gene leading to an accumulation of HIF 1 alpha. This allows growth factors such as VEGF and PDGF to be upregulated to promote angiogenesis and endothelial stabilization. Both sunitinib and sorafenib target VEGF and PDGF receptor tyrosine kinases while bevacizumab is a monoclonal antibody to VEGF. These three agents have demonstrated superior progression free survival in patients with metastatic RCC when compared to interferon or placebo. Newer anti-VEGF agents such as axitinib, pazopanib and cediranib are currently under investigation to elucidate future treatment options. The mammalian target of rapamycin (mTOR) is downstream of the VEGF pathway and has been targeted with drugs including temsirolimus and everolimus. This review will detail the pharmacologic and molecular activity of these agents and how they translate into clinical efficacy.
Heng
Daniel Y C
DY
Experimental Therapeutics, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44106, USA.
Bukowski
Ronald M
RM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D008024:Ligands; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases