Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma.
Clear-cell renal cell carcinoma (RCC) is characterized by the loss of von Hippel-Lindau disease protein and the resultant dysregulation of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), platelet-derived growth factor-beta (PDGF-beta)/PDGF receptor-beta (PDGFR-beta), and transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR)/Raf pathways, which contribute to angiogenesis, lymphangiogenesis, and tumor cell growth and survival. Significant advances in the treatment of clear-cell RCC have been derived from agents that target these pathways, including the multiple-kinase inhibitors (MKIs) sorafenib, sunitinib, and AG013736, which target multiple VEGFRs as well as PDGFR-beta. Sorafenib has the added advantage of inhibiting multiple different Raf isoforms, which enables it to target TGF-alpha/EGFR signaling and may also enhance its inhibition of VEGFR and PDGFR-beta. This review will examine the recent advances in our understanding of the biology of clear-cell RCC and show how those advances have helped delineate new targets of opportunity for treatment. It will also present the early clinical results of agents that target the pathways dysregulated in clear-cell RCC, with special emphasis on sorafenib and the other active MKIs, and will describe the scientific rationales for ongoing and future sorafenib-based combination therapy trials in RCC.
Gollob
Jared A
JA
Division of Medical Oncology Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. gollo001@mc.duke.edu
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D016211:Transforming Growth Factor alpha / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D066246:ErbB Receptors