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Sorafenib: Targeting Multiple Tyrosine Kinases in Cancer

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Small Molecules in Oncology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 201))

Abstract

Sorafenib (BAY 43-9006, Nexavar®) is an oral multiple tyrosine kinase inhibitor. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the Raf–Ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities.

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Notes

  1. 1.

    Source Fachinfo Nexavar® February 2013.

References

  • Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293–4300

    CAS  PubMed  Google Scholar 

  • Adjei AA, Molina JR, Mandrekar SJ, Marks R, Reid JR, Croghan G et al (2007) Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer. Clin Cancer Res 13:2684–2691

    CAS  PubMed  Google Scholar 

  • Ahmed M, Barbachano Y, Riddell A, Hickey J, Newbold KL, Viros A et al (2011) Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol 165:315–322

    CAS  PubMed  Google Scholar 

  • Aragon-Ching JB, Jain L, Gulley JL, Arlen PM, Wright JJ, Steinberg SM et al (2009) Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer. BJU Int 103:1636–1640

    CAS  PubMed Central  PubMed  Google Scholar 

  • Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y et al (2007) Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 21:439–445

    CAS  PubMed  Google Scholar 

  • Azad NS, Posadas EM, Kwitkowski VE, Steinberg SM, Jain L, Annunziata CM et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26:3709–3714

    CAS  PubMed  Google Scholar 

  • Baselga J, Segalla JG, Roche H, Del Giglio A, Pinczowski H, Ciruelos EM et al (2012) Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol 30:1484–1491

    CAS  PubMed  Google Scholar 

  • Beardsley EK, Hotte SJ, North S, Ellard SL, Winquist E, Kollmannsberger C et al (2012) A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer. Invest New Drugs 30:1652–1659

    CAS  PubMed  Google Scholar 

  • Bhatia S, Moon J, Margolin KA, Weber JS, Lao CD, Othus M et al (2012) Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512. PLoS One 7:e48787

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, Siena S et al (2009) Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs 20:616–624

    CAS  PubMed  Google Scholar 

  • Bodnar L, Gornas M, Szczylik C (2011) Sorafenib as a third line therapy in patients with epithelial ovarian cancer or primary peritoneal cancer: a phase II study. Gynecol Oncol 123:33–36

    CAS  PubMed  Google Scholar 

  • Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ et al (2011) Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica 96:62–68

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brose MS, Nutting CM, Sherman SI, Shong YK, Smit JW, Reike G et al (2011) Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer 11:349

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brose MS, Nutting C, Jarzab B, Elisei R, Siena S, Bastholt L et al (2013) Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: the phase III DECISION trial. J Clin Oncol 31:4

    Google Scholar 

  • Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A et al (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 57:821–829

    CAS  PubMed  Google Scholar 

  • Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM et al (2006) BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–334

    CAS  PubMed  Google Scholar 

  • Carlo-Stella C, Locatelli SL, Giacomini A, Cleris L, Saba E, Righi M et al (2013) Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways in tumor and vascular cells. PLoS One 8:e61603

    CAS  PubMed Central  PubMed  Google Scholar 

  • Carter CA, Chen C, Brink C, Vincent P, Maxuitenko YY, Gilbert KS et al (2007) Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Cancer Chemother Pharmacol 59:183–195

    CAS  PubMed  Google Scholar 

  • Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D et al (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574

    CAS  PubMed  Google Scholar 

  • Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34

    CAS  PubMed  Google Scholar 

  • Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS et al (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 48:1452–1465

    CAS  PubMed  Google Scholar 

  • Chi KN, Ellard SL, Hotte SJ, Czaykowski P, Moore M, Ruether JD et al (2008) A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer. Ann Oncol 19:746–751

    CAS  PubMed  Google Scholar 

  • Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472–5480

    CAS  PubMed  Google Scholar 

  • Crump M, Hedley D, Kamel-Reid S, Leber B, Wells R, Brandwein J et al (2010) A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) clinical trials group study. Leuk Lymphoma 51:252–260

    CAS  PubMed  Google Scholar 

  • Dahut WL, Scripture C, Posadas E, Jain L, Gulley JL, Arlen PM et al (2008) A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 14:209–214

    CAS  PubMed  Google Scholar 

  • Dasari A, Gore L, Messersmith WA, Diab S, Jimeno A, Weekes CD et al (2013) A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Invest New Drugs 31:115–125

    CAS  PubMed  Google Scholar 

  • Davies JM, Dhruva NS, Walko CM, Socinski MA, Bernard S, Hayes DN et al (2011) A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients. Lung Cancer 71:151–155

    PubMed Central  PubMed  Google Scholar 

  • Dingemans AM, Mellema WW, Groen HJ, van Wijk A, Burgers SA, Kunst PW et al (2013) A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation. Clin Cancer Res 19:743–751

    CAS  PubMed  Google Scholar 

  • Egberts F, Gutzmer R, Ugurel S, Becker JC, Trefzer U, Degen A et al (2011) Sorafenib and pegylated interferon-alpha2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial. Ann Oncol 22:1667–1674

    CAS  PubMed  Google Scholar 

  • Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R et al (2006) Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 95:581–586

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ellis PM, Al-Saleh K (2012) Multitargeted anti-angiogenic agents and NSCLC: clinical update and future directions. Crit Rev Oncol Hematol 84:47–58

    PubMed  Google Scholar 

  • Elser C, Siu LL, Winquist E, Agulnik M, Pond GR, Chin SF et al (2007) Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 25:3766–3773

    CAS  PubMed  Google Scholar 

  • Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M et al (2007a) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    CAS  PubMed  Google Scholar 

  • Escudier B, Lassau N, Angevin E, Soria JC, Chami L, Lamuraglia M et al (2007b) Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res 13:1801–1809

    CAS  PubMed  Google Scholar 

  • Flaherty KT, Schiller J, Schuchter LM, Liu G, Tuveson DA, Redlinger M et al (2008) A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res 14:4836–4842

    CAS  PubMed  Google Scholar 

  • Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R et al (2013) Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31:373–379

    CAS  PubMed  Google Scholar 

  • Friday BB, Adjei AA (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14:342–346

    CAS  PubMed  Google Scholar 

  • Furuse J, Ishii H, Nakachi K, Suzuki E, Shimizu S, Nakajima K (2008) Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci 99:159–165

    CAS  PubMed  Google Scholar 

  • Gitlitz BJ, Glisson BS, Moon J, Reimers H, Gandara DR (2008) Sorafenib in patients with platinum (plat) treated extensive stage small cell lung cancer (E-SCLC): A SWOG (S0435) phase II trial. J Clin Oncol 26:8039

    Google Scholar 

  • Gollob JA, Wilhelm S, Carter C, Kelley SL (2006) Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33:392–406

    CAS  PubMed  Google Scholar 

  • Gradishar WJ (2012) Sorafenib in locally advanced or metastatic breast cancer. Expert Opin Investig Drugs 21:1177–1191

    CAS  PubMed  Google Scholar 

  • Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S et al (2013) A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer 49:312–322

    CAS  PubMed  Google Scholar 

  • Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K et al (2008) Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26:4714–4719

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hainsworth JD, Ervin T, Friedman E, Priego V, Murphy PB, Clark BL et al (2010) Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer 116:3663–3669

    CAS  PubMed  Google Scholar 

  • Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P et al (2009) Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 27:2823–2830

    CAS  PubMed  Google Scholar 

  • Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    CAS  PubMed  Google Scholar 

  • Hu S, Niu H, Inaba H, Orwick S, Rose C, Panetta JC et al (2011) Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia. J Natl Cancer Inst 103:893–905

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hutson T, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman K et al (2012) Temsirolimus vs sorafenib as second line therapy in metastatic renal cell carcinoma: results from the intorsect trial. Ann Oncol 23:LBA22 PR

    Google Scholar 

  • Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP et al (2011) Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol 29:3293–3300

    CAS  PubMed Central  PubMed  Google Scholar 

  • Isaacs C, Herbolsheimer P, Liu MC, Wilkinson M, Ottaviano Y, Chung GG et al (2011) Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aromatase inhibitor resistant metastatic breast cancer. Breast Cancer Res Treat 125:137–143

    CAS  PubMed Central  PubMed  Google Scholar 

  • Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F et al (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23:6292–6298

    CAS  PubMed  Google Scholar 

  • Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA et al (2007) Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther 6:1785–1792

    CAS  PubMed  Google Scholar 

  • Kuiper JL, Lind JS, Groen HJ, Roder J, Grigorieva J, Roder H et al (2012) VeriStrat((R)) has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib. Br J Cancer 107:1820–1825

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA et al (2005) Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 5:188–196

    PubMed  Google Scholar 

  • Leach JW, Swenson K, Anderson E, Menge MR, Tsai ML (2010) A phase I study of weekly topotecan (T) in combination with sorafenib (S) for treatment of relapsed or refractory small cell lung cancer (SCLC). J Clin Oncol 28:e18086

    Google Scholar 

  • Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F et al (2012) Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American brain tumor consortium study 05-02. Neuro Oncol 14:1511–1518

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D et al (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851–11858

    CAS  PubMed  Google Scholar 

  • Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    CAS  PubMed  Google Scholar 

  • Macdonald DA, Assouline SE, Brandwein J, Kamel-Reid S, Eisenhauer EA, Couban S et al (2013) A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk Lymphoma 54:760–766

    CAS  PubMed  Google Scholar 

  • Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC et al (2012) Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood 119:5133–5143

    CAS  PubMed  Google Scholar 

  • Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL 3rd, Othus M et al (2012) Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). Clin Cancer Res 18:1129–1137

    CAS  PubMed Central  PubMed  Google Scholar 

  • Massard C, Zonierek J, Gross-Goupil M, Fizazi K, Szczylik C, Escudier B (2010) Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 21:1027–1031

    CAS  PubMed  Google Scholar 

  • Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D et al (2011) Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol 29:69–75

    PubMed Central  PubMed  Google Scholar 

  • McDermott DF, Sosman JA, Gonzalez R, Hodi FS, Linette GP, Richards J et al (2008) Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol 26:2178–2185

    CAS  PubMed  Google Scholar 

  • McInnes C, Sykes BD (1997) Growth factor receptors: structure, mechanism, and drug discovery. Biopolymers 43:339–366

    CAS  PubMed  Google Scholar 

  • Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A et al (2009) Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 113:6567–6571

    CAS  PubMed  Google Scholar 

  • Metzelder S, Finck A, Fey M, Scholl S, Kroger M, Reiter A et al (2010) Sorafenib monotherapy is effective in relapsed and refractory Flt3-ITD positive acute myeloid leukemia, particularly after allogenic stem cell transplantation. ASH Annual Meeting Abstracts 116:3314

    Google Scholar 

  • Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Gotze K et al (2012) High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 26:2353–2359

    CAS  PubMed  Google Scholar 

  • Minami H, Kawada K, Ebi H, Kitagawa K, Kim YI, Araki K et al (2008) Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci 99:1492–1498

    CAS  PubMed  Google Scholar 

  • Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O et al (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16:1688–1694

    CAS  PubMed  Google Scholar 

  • Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M et al (2009) Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol 27:11–15

    CAS  PubMed Central  PubMed  Google Scholar 

  • Motzer RJ, Nosov D, Eisen T, Bondarenko IN, Lesovoy V, Lipatov ON et al (2012) Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. J Clin Oncol 30:4501

    Google Scholar 

  • Motzer RJ, Eisen T, Hutson TE, Szczylik C, Krygowski M, Strahs AL et al (2013a) Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma. J Clin Oncol 31:350

    Google Scholar 

  • Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S et al (2013b) Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase III trial. Lancet Oncol 14:552–562

    CAS  PubMed  Google Scholar 

  • Mross K, Steinbild S, Baas F, Gmehling D, Radtke M, Voliotis D et al (2007) Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. Eur J Cancer 43:55–63

    CAS  PubMed  Google Scholar 

  • Navid F, Baker SD, McCarville MB, Stewart CF, Billups CA, Wu J et al (2013) Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Clin Cancer Res 19:236–246

    CAS  PubMed Central  PubMed  Google Scholar 

  • Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T et al (1995) Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res 55:4182–4187

    CAS  PubMed  Google Scholar 

  • Okamoto I, Miyazaki M, Morinaga R, Kaneda H, Ueda S, Hasegawa Y et al (2010) Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Invest New Drugs 28:844–853

    CAS  PubMed Central  PubMed  Google Scholar 

  • Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J et al (2012) Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 30:3084–3092

    CAS  PubMed  Google Scholar 

  • Polcher M, Eckhardt M, Coch C, Wolfgarten M, Kubler K, Hartmann G et al (2010) Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer. Cancer Chemother Pharmacol 66:203–207

    PubMed  Google Scholar 

  • Ramasubbaiah R, Perkins SM, Schilder J, Whalen C, Johnson CS, Callahan M et al (2011) Sorafenib in combination with weekly topotecan in recurrent ovarian cancer, a phase I/II study of the Hoosier Oncology Group. Gynecol Oncol 123:499–504

    CAS  PubMed  Google Scholar 

  • Ranze O, Hofmann E, Distelrath A, Hoeffkes HG (2007) Renal cell cancer presented with leptomeningeal carcinomatosis effectively treated with sorafenib. Onkologie 30:450–451

    PubMed  Google Scholar 

  • Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL et al (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505–2512

    CAS  PubMed  Google Scholar 

  • Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY et al (2010) Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 28:1856–1862

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA et al (2013) Phase II study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 121(23):4655–4662

    Google Scholar 

  • Reardon DA, Vredenburgh JJ, Desjardins A, Peters K, Gururangan S, Sampson JH et al (2011) Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol 101:57–66

    CAS  PubMed Central  PubMed  Google Scholar 

  • Richly H, Henning BF, Kupsch P, Passarge K, Grubert M, Hilger RA et al (2006) Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 17:866–873

    CAS  PubMed  Google Scholar 

  • Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase III trial. Lancet 378:1931–1939

    CAS  PubMed  Google Scholar 

  • Rollig C, Brandts C, Shaid S, Hentrich M, Kramer A, Junghanss C et al (2012) Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia. Leuk Lymphoma 53:1062–1067

    PubMed  Google Scholar 

  • Safaian NN, Czibere A, Bruns I, Fenk R, Reinecke P, Dienst A et al (2009) Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 33:348–350

    CAS  PubMed  Google Scholar 

  • Safarinejad MR (2008) Safety and efficacy of sorafenib in patients with castrate resistant prostate cancer: a phase II study. Urol Oncol 28:21–27

    Google Scholar 

  • Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G et al (2006) BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res 12:1623–1629

    CAS  PubMed  Google Scholar 

  • Savage DG, Antman KH (2002) Imatinib mesylate—a new oral targeted therapy. N Engl J Med 346:683–693

    CAS  PubMed  Google Scholar 

  • Savvides P, Nagaiah G, Lavertu P, Fu P, Wright JJ, Chapman R et al (2013) Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid 23:600–604

    CAS  PubMed  Google Scholar 

  • Sayar H, Cripe L, Cangany M, Weisenbach J, Sargent KJ, Goswami C et al (2010) Cyclic administration of combination of sorafenib and vorinostat in poor-risk AML: a pharmacodynamically-oriented extended phase I trial. ASH Annu Meet Abs 116:3272

    Google Scholar 

  • Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M et al (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 28:1835–1842

    CAS  PubMed  Google Scholar 

  • Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit JW, Kapiteijn E (2012) Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol 167:643–650

    CAS  PubMed  Google Scholar 

  • Schroeder T, Zohren F, Saure C, Bruns I, Czibere A, Safaian NN et al (2010) Sorafenib treatment in 13 patients with acute myeloid leukemia and activating FLT3 mutations in combination with chemotherapy or as monotherapy. Acta Haematol 124:153–159

    PubMed  Google Scholar 

  • Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT et al (2013) Sorafenib or Placebo with Either Gemcitabine or Capecitabine in Patients with HER-2-Negative Advanced Breast Cancer That Progressed during or after Bevacizumab. Clin Cancer Res 19:2745–2754

    CAS  PubMed  Google Scholar 

  • Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947

    CAS  PubMed  Google Scholar 

  • Serve H, Wagner R, Sauerland C, Brunnberg U, Krug U, Schaich M et al (2010) Sorafenib in combination with standard induction and consolidation therapy in elderly AML patients: results from a randomized, placebo-controlled phase II trial. ASH Ann Meet Abs 116:333

    Google Scholar 

  • Sharma M, Ravandi F, Bayraktar UD, Chiattone A, Bashir Q, Giralt S et al (2011) Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant 17:1874–1877

    CAS  PubMed  Google Scholar 

  • Sharma N, Pennell NA, Halmos B, Ma PM, Dowlati A (2012) Phase II trial of sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive-stage small cell lung cancer (SCLC): Final results. J Clin Oncol 30:e17563

    Google Scholar 

  • Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T et al (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12:144–151

    CAS  PubMed  Google Scholar 

  • Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R et al (2008) CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene 28(1):85–94

    Google Scholar 

  • Spigel DR, Hainsworth JD, Burris HA 3rd, Molthrop DC, Peacock N, Kommor M et al (2011) A pilot study of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel and sorafenib in women with node-positive or high-risk early-stage breast cancer. Clin Adv Hematol Oncol 9:280–286

    PubMed  Google Scholar 

  • Steinbild S, Mross K, Frost A, Morant R, Gillessen S, Dittrich C et al (2007) A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Br J Cancer 97:1480–1485

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stirewalt DL, Radich JP (2003) The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3:650–665

    CAS  PubMed  Google Scholar 

  • Strumberg D, Voliotis D, Moeller JG, Hilger RA, Richly H, Kredtke S et al (2002) Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. Int J Clin Pharmacol Ther 40:580–581

    CAS  PubMed  Google Scholar 

  • Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M et al (2005) Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23:965–972

    CAS  PubMed  Google Scholar 

  • Sugiyama H, Onuki K, Ishige K, Baba N, Ueda T, Matsuda S et al (2011) Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells. J Gastroenterol 46:779–789

    CAS  PubMed  Google Scholar 

  • Valabrega G, Capellero S, Cavalloni G, Zaccarello G, Petrelli A, Migliardi G et al (2011) HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Res Treat 130:29–40

    CAS  PubMed  Google Scholar 

  • Valcamonico F, Ferrari V, Amoroso V, Rangoni G, Simoncini E, Marpicati P et al (2008). Long-lasting successful cerebral response with sorafenib in advanced renal cell carcinoma. J Neurooncol 91:47–50

    Google Scholar 

  • Wakelee HA, Lee JW, Hanna NH, Traynor AM, Carbone DP, Schiller JH (2012) A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501. J Thorac Oncol 7:1574–1582

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW et al (2008) Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 14:5124–5130

    CAS  PubMed  Google Scholar 

  • Welch SA, Hirte HW, Elit L, Schilder RJ, Wang L, Macalpine K et al (2010) Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium. Int J Gynecol Cancer 20:787–793

    PubMed  Google Scholar 

  • Widemann BC, Kim A, Fox E, Baruchel S, Adamson PC, Ingle AM et al (2012) A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children’s Oncology Group Phase I Consortium report. Clin Cancer Res 18:6011–6022

    CAS  PubMed  Google Scholar 

  • Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H et al (2004) 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 64:7099–7109

    CAS  PubMed  Google Scholar 

  • Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844

    CAS  PubMed  Google Scholar 

  • Williamson SK, Moon J, Huang CH, Guaglianone PP, LeBlanc M, Wolf GT et al (2010) Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol 28:3330–3335

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D et al (2008) DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res 36:D901–D906

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X et al (2008) Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 100:184–198

    CAS  PubMed  Google Scholar 

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  1. Department Innere Medizin, Klinik für Innere Medizin I, Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation, Hugstetter Str. 55, 79102, Freiburg, Germany

    Jens Hasskarl

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    Uwe M. Martens

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Hasskarl, J. (2014). Sorafenib: Targeting Multiple Tyrosine Kinases in Cancer. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54490-3_8

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