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Targeted Agents and Systemic Therapy in Hepatocellular Carcinoma

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Multidisciplinary Treatment of Hepatocellular Carcinoma

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 190))

Abstract

Cytotoxic chemotherapy, hormonal agents, and immunotherapy have been tested in hepatocellular cancer (HCC) with marginal efficacy to date. Recent insights into the molecular pathogenesis of HCC have identified several aberrant signaling pathways that have served as targets for novel therapeutic agents. These discoveries have been translated into the clinical realm with the use of the antiangiogenic and the Raf kinase inhibitor, sorafenib, and have revealed the potential of targeted agents to produce clinically meaningful survival benefits in patients with advanced HCC. Efforts continue in the quest to improve the outcome of HCC patients through the development and evaluation of other targeted agents, and to better understand the interactions between the underlying disease biology and response to therapy. Several pathways are now implicated in hepatocarcinogenesis and agents that target these pathways continue to be developed.

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References

  1. GLOBOCAN 2008 (IARC). Section of cancer information. Accessed 19 Nov 2010

    Google Scholar 

  2. Abou-Alfa GK, Venook AP (2008) The impact of new data in the treatment of advanced hepatocellular carcinoma. Curr Oncol Rep 10(3):199–205

    Article  PubMed  CAS  Google Scholar 

  3. Huitzil-Melendez FD, Capanu M, O'Reilly EM et al. 2010 Advanced hepatocellular carcinoma: which staging system best predicts prognosis. J Clin Oncol 28(17):2889–2895

    Article  PubMed  Google Scholar 

  4. Chenivesse X, Franco D, Brechot C(1993s): MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis. J Hepatol 18:168–172

    Google Scholar 

  5. Soini Y, Virkajarvi N, Raunio H et al (1996) Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis. J Clin Pathol 49:470–473

    Article  PubMed  CAS  Google Scholar 

  6. DeVita VT Jr (2000) Therapeutic implications of the new biology. Cancer J 6(Suppl 2):S113–S120

    PubMed  Google Scholar 

  7. Jiang W, Lu Z, He Y et al (1997) Dihydropyrimidine dehydrogenase activity in hepatocellular carcinoma: implication in 5-fluorouracil-based chemotherapy. Clin Cancer Res 3:395–399

    PubMed  CAS  Google Scholar 

  8. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759

    Article  PubMed  CAS  Google Scholar 

  9. Whittaker S, Marais R, Zhu AX (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29:4989–5005

    Article  PubMed  CAS  Google Scholar 

  10. Oster S, Penn L, Stambolic V (2005) Oncogenes and tumor suppressor genes. In: Tannock IF et al (eds.) Basic science of oncology, 4th edn. McGraw-Hill Medical Publishing Division, Toronto, pp 123–141

    Google Scholar 

  11. Schlessinger J (2002) Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110:669–672

    Article  PubMed  CAS  Google Scholar 

  12. Ito Y, Takeda T, Sakon M et al (2001) Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 84(10):1377–83

    Article  PubMed  CAS  Google Scholar 

  13. Wellcome Trust Genome Campus (2011) Sanger Institute. Catalogue Of Somatic Mutations In Cancer (COSMIC) database http://www.sanger.ac.uk/genetics/CGP/cosmic/

  14. Feitelson MA, Pan J, Lian Z (2004) Early molecular and genetic determinants of primary liver malignancy. Surg Clin North Am 84:339–354

    Article  PubMed  Google Scholar 

  15. Castillo J, Erroba E, Perugorria MJ et al (2006) Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res 66(12):6129–38

    Article  PubMed  CAS  Google Scholar 

  16. Philip PA, Mahoney MR, Allmer C et al (2005) Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23:6657–63

    Article  PubMed  CAS  Google Scholar 

  17. O’Dwyer PJ, Biantonio BJ, Levy DE et al (2006) Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s Study E1203. J Clin Oncol ASCO Ann Meet Proc Part I 24(18S) (June 20 Supplement):4143

    Google Scholar 

  18. Ramanathan RK, Belani CP, Singh DA et al (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64(4):777–83

    Article  PubMed  CAS  Google Scholar 

  19. Huether A, Hopfner M, Varadari V et al (2005) EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular carcinoma. Biochem Pharmacol 70:1568–1578

    Article  PubMed  CAS  Google Scholar 

  20. Gruenwald V, Wilkens L, Gebel M et al (2007) A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: final results. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. vol 25(18S) (June 20 Supplement):4598

    Google Scholar 

  21. Zhu AX, Stuart K, Blaszkowsky LS et al (2007) Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110(3):581–9

    Article  PubMed  CAS  Google Scholar 

  22. O’Neil BH, Bernard SA, Goldberg RM et al (2008) Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma. J Clin Oncol 26:(May 20 suppl; abstr 4604)

    Google Scholar 

  23. Louafi S, Hebbar M, Rosmorduc O et al (2007) Gemcitabine, oxaliplatin (GEMOX) and cetuximab for treatment of hepatocellular carcinoma (HCC): results of the phase II study ERGO. J Clin Oncol 2007 ASCO Annu Meet Proc Part I vol 25(18S) (June 20 Supplement):4594

    Google Scholar 

  24. Asnacios A, Fartoux L, Romano O et al (2008) Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study. Cancer 112(12):2733–9

    Article  PubMed  CAS  Google Scholar 

  25. Hursting SD, Berger NA (2010) Energy balance, Host-related factors, and cancer progression. J Clin Oncol 28(26):4058–4065. Epub 9 Aug 2010, 10 Sept 2010

    Google Scholar 

  26. Pollak M (2009) Insulin and insulin-like growth factor signalling in neoplasia nature reviews cancer 8:915–928 (Dec 2008). Erratum in: nature reviews cancer 9:224 (Mar 2009)

    Google Scholar 

  27. Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17:328–336

    Article  PubMed  CAS  Google Scholar 

  28. Desbois-Mouthon C, Cacheux W (2006) Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 119:2557–66

    Article  PubMed  CAS  Google Scholar 

  29. Kuribayashi A, Kataoka K, Kurabayashi T, Miura M (2004) Evidence that basal activity, but not transactivation, of the epidermal growth factor receptor tyrosine kinase is required for insulin-like growth factor I-induced activation of extracellular signal-regulated kinase in oral carcinoma cells. Endocrinology 145(11):4976–84

    Article  PubMed  CAS  Google Scholar 

  30. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93(24):1852–57

    Article  PubMed  CAS  Google Scholar 

  31. Slomiany MG, Blck LA, Kibbey MM et al (2006) IGF-1 induced vascular endothelial growth factor secretion in head an dneck squamous cell carcinoma. Biochem Biophys Res Commun 342(3):851–858

    Google Scholar 

  32. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël MJ et al (2009) Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res;15(17):5445–5456. Epub 25 Aug 2009

    Google Scholar 

  33. O’Donnell R, El-Khoueiry AB, Lenz H et al (2010) A phase I trial of escalating doses of the anti-IGF-1R monoclonal antibody (mAb) cixutumumab (IMC-A12) and sorafenib for treatment of advanced hepatocellular carcinoma (HCC). J Clin Oncol 28:15s (suppl; abstr TPS212)

    Google Scholar 

  34. Matsumoto K, Nakamura T (1996) Emerging multipotent aspects of hepatocyte growth factor. J Biochem 119(4):591–600

    Article  PubMed  CAS  Google Scholar 

  35. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  PubMed  CAS  Google Scholar 

  36. Wang R, Ferrell LD, Faouzi S et al (2001) Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol 153(5):1023–1034

    Google Scholar 

  37. Salvi A, Arici B, Portolani N et al (2007) In vitro c-met inhibition by antisense RNA and plasmid-based RNAi down-modulates migration and invasion of hepatocellular carcinoma cells. Int J Oncol 31(2):451–60

    PubMed  CAS  Google Scholar 

  38. Heideman DA, Overmeer RM, van Beusechem VW et al (2005) Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy. Cancer Gene Ther 12(12):954–62

    Article  PubMed  CAS  Google Scholar 

  39. Salvi A, Sabelli C, Moncini S et al (2009) MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS J 276(11):2966–2982. Epub 16 Apr, Jun 2009

    Google Scholar 

  40. Wang SY, Chen B, Zhan YQ, Xu WX et al (2004) SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells. J Hepatol 41(2):267–73

    Article  PubMed  CAS  Google Scholar 

  41. Boix L, Rosa JL, Ventura F, Castells A, Bruix J, Rode′s J et al (1994) c-MET mRNA overexpression in human hepatocellular carcinoma. Hepatology 19:88–91

    Google Scholar 

  42. Kiss A, Wang NJ, Xie JP, Thorgeirsson SS (1997) Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 3:1059–1066

    PubMed  CAS  Google Scholar 

  43. Suzuki K, Hayashi N, Yamada Y et al (1994) Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology 20:1231–1236

    Article  PubMed  CAS  Google Scholar 

  44. Tavian D, De PG, Benetti A et al (2000) u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J Cancer 87:644–649

    Google Scholar 

  45. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E (1997) Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology 25:619–623

    Article  PubMed  CAS  Google Scholar 

  46. Huitzil FD, Sun MY, Capanu M et al (2008) Expression of the c-met and HGF in resected hepatocellular carcinoma (rHCC): correlation with clinicopathological features (CP) and overall survival (OS). J Clin Oncol 26:(May 20 suppl; abstr 4599)

    Google Scholar 

  47. Kaposi-Novak P, Lee JS, Gomez-Quiroz L et al (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595

    Article  PubMed  CAS  Google Scholar 

  48. Borbath I, Santoro A, Van Laethem J et al (2010) ARQ 197–215: A randomized, placebo-controlled phase II clinical trial evaluating the c-Met inhibitor, ARQ 197, in patients (pts) with hepatocellular carcinoma (HCC). J Clin Oncol 28:15s, (suppl; abstr TPS215)

    Google Scholar 

  49. Mitsuhashi N, Shimizu H, Ohtsuka M et al (2003) Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology 37(5):1105–13

    Article  PubMed  CAS  Google Scholar 

  50. Zhang T, Sun HC, Xu Y et al (2005) Overexpression of platelet-derived growth factor receptor alpha in endothelial cells of hepatocellular carcinoma associated with high metastatic potential. Clin Cancer Res 11:8557–8563

    Article  PubMed  CAS  Google Scholar 

  51. Sturk C, Dumont D (2005) Angiogenesis. In: Tannock IF et al. (eds.) Basic science of oncology. McGraw-Hill Medical Publishing Division, Toronto, pp 231–248

    Google Scholar 

  52. Bangoura G, Liu ZS, Qian Q et al (2007) Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 13:3176–3182

    PubMed  CAS  Google Scholar 

  53. Avila MA, Berasain C, Sangro B, Prieto J (2006) New therapies for hepatocellular carcinoma. Oncogene 25:3866–3884

    CAS  Google Scholar 

  54. Lian Z, Liu J, Wu M et al (2007) Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis. Hepatology 45:1390–1399

    Article  PubMed  CAS  Google Scholar 

  55. El-Assal ON, Yamanoi A, Soda Y et al (1998) Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27:1554–1562

    Article  PubMed  CAS  Google Scholar 

  56. Li XM, Tang ZY, Zhou G et al (1998) Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res 17:13–17

    PubMed  Google Scholar 

  57. Yamaguchi R, Yano H, Iemura A et al (1998) Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28:68–77

    Google Scholar 

  58. Zhou J, Tang ZY, Fan J et al (2000) Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus. J Cancer Res Clin Oncol 126:57–61

    Article  PubMed  CAS  Google Scholar 

  59. Dhar DK, Naora H, Yamanoi A et al (2002) Requisite role of VEGF receptors in angiogenesis of hepatocellular carcinoma: a comparison with angiopoietin/Tie pathway. Anticancer Res 22(1A):379–386

    Google Scholar 

  60. Poon RT, Lau C, Yu WC et al (2004) High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep 11(5):1077–84

    PubMed  CAS  Google Scholar 

  61. Chao Y, Li CP, Chao GY et al (2003) Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 10:355–362

    Article  PubMed  Google Scholar 

  62. Ellis LM, Hicklin DJ (2008 Aug) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–91

    Article  CAS  Google Scholar 

  63. Malka D, Dromain C, Farace F et al (2007) Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. J Clin Oncol 2007 ASCO Annu Meet Proc Part I vol 25(18S) (June 20 Supplement):4570

    Google Scholar 

  64. Siegel AB, Cohen EI, Ocean A et al (2008) Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 26(18):2992–8

    Article  PubMed  CAS  Google Scholar 

  65. Schwartz JD, Schwartz M, Lehrer D et al (2006) Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. J Clin Oncol 2006 ASCO Annu Meet Proc Part I vol 24(18S)(June 20 Supplement):4144

    Google Scholar 

  66. Zhu AX, Blaszkowsky LS, Ryan DP et al (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:1898–903

    Article  PubMed  CAS  Google Scholar 

  67. Sun W, Haller DG, Mykulowycz K et al (2007) Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. J Clin Oncol 2007 ASCO Annu Meet Proc Part I 25(18S) (June 20 Supplement):4574

    Google Scholar 

  68. Thomas MB, Morris JS, Chadha R et al (2009) Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 27(6):843–850. Epub 12 Jan 2009. Erratum in: J Clin Oncol Jul 1 27(19):3263. Lin, Elinor [corrected to Lin, E]

    Google Scholar 

  69. Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  70. Abou-Alfa GK, Schwartz L, Ricci S et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular Carcinoma. J Clin Oncol 24:1–8

    Article  Google Scholar 

  71. Zhao B (2006) Shape-constraint region-growing for delineation of hepatic metastases on contrast-enhanced CT scans. Invest Radiol 41(10):753–62

    Article  PubMed  Google Scholar 

  72. Abou-Alfa GK, Zhao B, Capanu M et al (2008) Tumor necrosis as a correlate for response 916 in subgroup of patients with Advanced Hepatocellular Carcinoma (HCC) Treated with 917 Sorafenib. ESMO, Sweden, p 547

    Google Scholar 

  73. Llovet JM, Ricci S, Mazzaferro V (2008) SHARP investigators study group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–90

    Article  PubMed  CAS  Google Scholar 

  74. Cheng AL, Kang YK, Chen Z 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(1):25–34

    Article  PubMed  CAS  Google Scholar 

  75. Abou-Alfa GK (2009) Selection of patients with hepatocellular carcinoma for sorafenib. J Natl Compr Canc Netw 7(4):397–403

    PubMed  CAS  Google Scholar 

  76. Bolondi L, Caspary W, Bennouna J et al (2008) Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): Subgroup analysis of the SHARP trial. Gastrointestinal Cancers Symposium, abstract 129

    Google Scholar 

  77. Giambartolomei S, Covone F, Levrero M, Balsano C (2001) Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 20(20):2606–10

    Article  PubMed  CAS  Google Scholar 

  78. Huitzil FD, Saltz LS, Song J et al (2008) Retrospective analysis of outcome in hepatocellular carcinoma (HCC) patients (pts) with Hepatitis C (C+) versus B (B+) treated with Sorafenib (S). Program and abstracts of the 2008 Gastrointestinal Cancers 945 Symposium; Orlando, Florida, Abstract, Jan 19–21

    Google Scholar 

  79. Abou-Alfa GK, Amadori D, Santoro A, Figer A, De Greve J, Lathia C, Voliotis D, Anderson S, Moscovici M, Ricci S (2011) Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest Cancer Res 4(2):40–44

    PubMed  Google Scholar 

  80. Miller AA, Murry DJ, Owzar K et al (2009) Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27(11):1800–5

    Article  PubMed  CAS  Google Scholar 

  81. Pinter M, Sieghart W, Graziadei I et al (January 2009) Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage Liver Cirrhosis. Oncologist 14(1):70–76

    Article  Google Scholar 

  82. Yau T, Chan P, Ng K et al (2008) Efficacy and tolerability of single agent sorafenib in poor risk advanced hepatocellular carcinoma patients. J Clin Oncol 26:(May 20 suppl; abstr 15513)

    Google Scholar 

  83. Abou-Alfa GK, Johnson P, Knox JJ et al (2010) Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304(19):2154–2160

    Article  PubMed  CAS  Google Scholar 

  84. Alavi AS, Acevedo L, Min W, Cheresh DA (2007) Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res 67(6):2766–72

    Article  PubMed  CAS  Google Scholar 

  85. McCubrey JA, Steelman LS, Abrams SL et al (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279

    Article  PubMed  CAS  Google Scholar 

  86. Hoffman K, Franz C, Xiao Z et al (2010) Sorafenib modulates the Gene expression of multi-drug resistance mediating ATP-Binding cassette proteins in experimental hepatocellular Carcinoma. Anticancer Res 30(11):4503–8

    Google Scholar 

  87. Duran I, Hotté SJ, Hirte H et al (2007) Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. Clin Cancer Res 13(16):4849–57

    Article  PubMed  CAS  Google Scholar 

  88. Zhu AX, Sahani DV, Duda DG et al (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27(18):3027–35

    Article  PubMed  CAS  Google Scholar 

  89. Faivre S, Raymond E, Boucher E et al (2009) Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multi-centre phase II study. Lancet Oncol 10(8):794–800

    Article  PubMed  CAS  Google Scholar 

  90. Raoul JL, Finn RS, Kang YK et al (2009) An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol 27:15s, (suppl; abstr 4577)

    Google Scholar 

  91. Finn RS, Kang Y, Park J et al (2009) Phase II, open label study of brivanib alaninate in patients (pts) with hepatocellular carcinoma (HCC) who failed prior antiangiogenic therapy. Gastrointestinal Cancers Symposium. Abstract 200

    Google Scholar 

  92. Finn RS, Raoul J, Manekas D et al (2010) Optimal assessment of treatment benefit with targeted agents for hepatocellular carcinoma (HCC): an analysis of brivanib phase II data. ASCO Annual Meeting. Abstract 4096.

    Google Scholar 

  93. Toh H, Chen P, Carr BI et al (2009) A phase II study of ABT-869 in hepatocellular carcinoma (HCC): Interim analysis. J Clin Oncol 27:15s (suppl; abstr 4581)

    Google Scholar 

  94. Toh H, Chen P, Carr BI et al (2010) Linifanib phase II trial in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 28:15s (suppl; abstr 4038)

    Google Scholar 

  95. Wood JM, Bold G, Buchdunger E et al (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60(8):2178–89

    PubMed  CAS  Google Scholar 

  96. Liu Y, Poon RT, Li Q et al (2005) Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 65(9):3691–9

    Article  PubMed  CAS  Google Scholar 

  97. Koch I, Baron A, Roberts S et al (2005) Influence of hepatic dysfunction on safety, tolerability, and pharmacokinetics (PK) of PTK787/ZK 222584 in patients (Pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 2005 ASCO Annu Meet Proc 23(16S) Part I of II (June 1 Supplement):4134

    Google Scholar 

  98. Wedge SR, Kendrew J, Hennequin LF et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–400

    Article  PubMed  CAS  Google Scholar 

  99. Alberts SR, Morlan BW, Kim GP et al (2007) NCCTG phase II trial (N044J) of AZD2171 for patients with hepatocellular carcinoma (HCC)–Interim review of toxicity.Gastrointestinal Cancers Symposium, abstract #186

    Google Scholar 

  100. 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

    Article  PubMed  CAS  Google Scholar 

  101. Leicht DT, Balan V, Kaplun A et al (2007) Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773:1196–1212

    Article  PubMed  CAS  Google Scholar 

  102. Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351(Part 2):289–305

    Google Scholar 

  103. Hwang YH, Choi JY, Kim S et al (2004) Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 29:113–121

    Article  PubMed  CAS  Google Scholar 

  104. Schuierer MM, Bataille F, Weiss TS et al (2006) Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 16:451–456

    PubMed  CAS  Google Scholar 

  105. Yoshida T, Hisamoto T, Akiba J et al (2006) Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. Oncogene 25:6056–6066

    Article  PubMed  CAS  Google Scholar 

  106. Aoki H, Hayashi J, Moriyama M et al (2000) Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J Virol 74:1736–1741

    Google Scholar 

  107. Stockl L, Berting A, Malkowski B et al (2003) Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression. Oncogene 22:2604–2610

    Article  PubMed  Google Scholar 

  108. Weihrauch M, Benick M, Lehner G et al (2001 Aug) High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride. Int Arch Occup Environ Health 74(6):405–10

    Article  CAS  Google Scholar 

  109. Kato K, Cox AD, Hisaka MM et al (1992) Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Nat Acad Sci USA 89(14):6403–7

    Article  PubMed  CAS  Google Scholar 

  110. McGill MA, McGlade CJ (2005) Cellular signaling. In: Tannock IF et al (eds.) Basic science of oncology. McGraw-Hill Medical Publishing Division, Toronto, pp 142–166

    Google Scholar 

  111. Carloni V, Vizzutti F, Pantaleo P (2005) Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Clin Cancer Res 11(11):4266–74

    Article  PubMed  CAS  Google Scholar 

  112. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343(6257):425–30

    Article  PubMed  CAS  Google Scholar 

  113. El-Serag HB, Johnson ML, Hachem C et al (2009) Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009 May;136(5):1601-1608. Epub Jan 30

    Google Scholar 

  114. Kawata S, Yamasaki E, Nagase T et al (2001) Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 84(7):886–91

    Article  PubMed  CAS  Google Scholar 

  115. Huynh H, Soo KC, Chow PK et al (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 6(1):138–46

    Article  PubMed  CAS  Google Scholar 

  116. Stambolic V, Suzuk A, de la Pompa JL et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39

    Article  PubMed  CAS  Google Scholar 

  117. Treiber G (2009) mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther 9(2):247–261

    Article  PubMed  CAS  Google Scholar 

  118. Villanueva A, Chiang DY, Newell P et al (Dec 2008) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135(6):1972–83

    Article  Google Scholar 

  119. Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90:1243–1250

    Article  PubMed  CAS  Google Scholar 

  120. Schmelzle T, Hall MN (2000) Tor: a central controller of cell growth. Cell 103:253–262

    Article  PubMed  CAS  Google Scholar 

  121. Roberts LR, Gores GJ (2006) Emerging drugs for hepatocellular carcinoma. Expert Opin Emerg Drugs 11:469–487

    Article  PubMed  CAS  Google Scholar 

  122. Baba H, Wohlschlaeger J, Cicinnati VR et al (2009) Phosphorylation of p70S6 kinase predicts survival in patients with clear-margin resected hepatocellular carcinoma. Liver Int 29(3):399–405

    Article  PubMed  CAS  Google Scholar 

  123. Chen YB, Sun YA, Gong JP (2008) Effects of rapamycin in liver transplantation. Hepatobiliary Pancreas Dis Int 7:25–28

    Google Scholar 

  124. Toso S, Merani S, Bigam DL, Shapiro AMJ, Kneteman NM (2010) Sirolimus-based immunosuppression is associated with increased survival after lier transplantation for hepatocellular carcinoma. Hepatology 51(4):127–1243

    Article  Google Scholar 

  125. Zhou J, Fan J, Wang Z et al (2006) Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: report of an initial experience. World J Gastroenterol 12:3114–3118

    PubMed  CAS  Google Scholar 

  126. Zimmerman MA, Trotter JF, Wachs M et al (2008) Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 14:633–638

    Article  PubMed  Google Scholar 

  127. Rizell M, Andersson M, Cahlin C, Hafstrom L, Olausson M, Lindner P (2008) Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 13:66–70

    Article  PubMed  CAS  Google Scholar 

  128. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours Revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Google Scholar 

  129. Leung TW, Patt YZ, Lau WY et al (1999) Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5(7):1676–81

    PubMed  CAS  Google Scholar 

  130. Benjamin RS, Choi H, Macapinlac HA et al (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25(13):1760–4

    Article  PubMed  Google Scholar 

  131. Bruix J, Sherman M, Llovet JM et al (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35(3):421–30

    Article  PubMed  CAS  Google Scholar 

  132. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42(5):1208–36

    Article  PubMed  Google Scholar 

  133. Lencioni R, Llovet JM (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30(1):52–60

    Article  PubMed  CAS  Google Scholar 

  134. Norden AD, Drappatz J, Muzikansky A et al (2009) An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 92:149–155

    Article  PubMed  CAS  Google Scholar 

  135. Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972

    Article  PubMed  Google Scholar 

  136. Abou-Alfa GK, Gultekin DH, Capanu M et al (2009) Association of dynamic contrast enhanced-MRI (DCE-MRI) with response in a subgroup of patients with advanced hepatocellular carcinoma (HCC) treated with doxorubicin plus sorafenib. Gastrointestinal Cancers Symposium, abstract #271

    Google Scholar 

  137. Rhee TK, Larson AC, Prasad PV et al (2005) Feasibility of blood oxygenation level-dependent MR imaging to monitor hepatic transcatheter arterial embolization in rabbits. J Vasc Interv Radiol 16(11):1523–8

    Article  PubMed  Google Scholar 

  138. Kamel IR, Bluemke DA, Eng J et al (2006) The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. J Vasc Interv Radiol 17(3):505–12

    Article  PubMed  Google Scholar 

  139. Ayyappan A, Jhaveri KS (2010) CT and MRI of hepatocellular carcinoma: an update. Expert Rev Anticancer Ther 10(4):507–19

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA

    Celina Ang, Eileen M. O’Reilly & Ghassan K. Abou-Alfa

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  1. Celina Ang
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  2. Eileen M. O’Reilly
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  3. Ghassan K. Abou-Alfa
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Correspondence to Ghassan K. Abou-Alfa .

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  1. M.D. Anderson Cancer Center, Dept. Surgical Oncology, University of Texas, Holcombe Blvd. 1515, Houston, 77030, Texas, USA

    Jean-Nicolas Vauthey

  2. , Dept. of Surgical Oncology, MD Anderson Cancer Center, Holcombe Boulevard, Unit 444 1515, Houston, 77030, USA

    Antoine Brouquet

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Ang, C., O’Reilly, E.M., Abou-Alfa, G.K. (2013). Targeted Agents and Systemic Therapy in Hepatocellular Carcinoma. In: Vauthey, JN., Brouquet, A. (eds) Multidisciplinary Treatment of Hepatocellular Carcinoma. Recent Results in Cancer Research, vol 190. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16037-0_15

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