![Relevant molecular targets of Sorafenib in NSCLC ŧ in vitro kinase assays ,[object Object],[object Object],[object Object],Wilhelm S, et al. Nat Rev Drug Discov . 2006; 5(10):835-44; Carter C, et al. Cancer Chemother Pharmacol 2007; 59(2):183-195 Serine/threonine Kinases ŧ Kinase IC 50 (nM) Raf-1 6 B-Raf 25 B-raf V600E 38 p38 38 ERK-1, MEK- 1, PKA, PKB, PKC, cdk1/cyclinB, pim-1 >10,000 Receptor Tyrosine Kinases ŧ Kinase IC 50 (nM) VEGFR-1 26 VEGFR-2 90 VEGFR-3 20 FLT3 33 RET 47 PDGFR- 57 C-KIT 68 FGFR-1 580 c-met, IGFR-1, EGFR, HER2 >10,000](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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Sorafenib
- 1. Sorafenib Targets Tumor Cell Proliferation and Angiogenesis Endothelial Cell or Pericyte Proliferation Migration Angiogenesis: Tubule formation PDGF- VEGF VEGFR-2 PDGFR- Paracrine stimulation Differentiation Mitochondria Apoptosis Tumor Cell PDGF VEGF Proliferation Survival Mitochondria HIF Nucleus Apoptosis ERK RAS MEK RAF Nucleus RAF Mcl-1 Avila MA, et al. Oncogene . 2006;25:3866-3884; Liu L, et al. Cancer Res . 2006;66:11851-11858; Semela D, et al. J Hepatol . 2004;41:864-880; Wilhelm SM, et al. Cancer Res . 2004;64:7099-7109. HGF HGF Autocrine loop Sorafenib Sorafenib HGF = hepatocyte growth factor. RAS ERK MEK
- 4. Ongoing Phase III Trials of Sorafenib in NSCLC MISSION Trial. Available at: www.clinicaltrials.gov. NCT00863746. http://www.clinicaltrials.gov/ct2/show/NCT00863746?term=NCT00863746&rank=1 NExUS Study. Available at: www.clinicaltrials.gov. NCT00449033. http://www.clinicaltrials.gov/ct2/show/NCT00449033?term=NCT00449033&rank=1 Primary endpoint : Overall survival Secondary endpoints : PFS, DCR, ORR, TTP, and patient-reported outcomes MISSION TRIAL Primary endpoint : Overall survival Secondary endpoints : PFS, safety, patient-reported outcomes NEXUS TRIAL Sorafenib 400 mg bid + best supportive care Placebo + best supportive care Sorafenib 400 mg bid + gemcitabine/cisplatin Placebo + gemcitabine/cisplatin
Editor's Notes
- Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res . 2004;64:7099-7109. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66:11851-11858. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene . 2006;25:3866-3884. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol . 2004;41:864-880.