Targeted Therapies for Hepatocellular Carcinoma

  • Jonas W. Feilchenfeldt
  • Eileen M. O’Reilly
  • Costantine Albany
  • Ghassan K. Abou-Alfa


The liver’s role in xenobiotic metabolism, i.e., the modification of drugs and toxic foreign compounds, has long served as a putated explanation for inherent drug resistance of hepatocellular carcinoma (HCC). Therefore, it does not come as a surprise that the initial discovery of the multiple-drug resistance gene (MDR) was in liver tissue [1], and hepatocyte cell lines are a natural reservoir for the study of drug resistance.


HCC targeted therapies Sorafenib Bevacizumab Sunitinib Tyrosine kinase inhibitors (TKIs) Erlotinib HCC etiology 


  1. 1.
    Thorgeirsson SS, Huber BE, Sorrell S, Fojo A, Pastan I, Gottesman MM (1987) Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science 236:1120–1122CrossRefPubMedGoogle Scholar
  2. 2.
    Lopez PM, Villanueva A, Llovet JM (2006) Systematic review: evidence-based management of hepatocellular carcinoma—an updated analysis of randomized controlled trials. Aliment Pharmacol Ther 23:1535–1547CrossRefPubMedGoogle Scholar
  3. 3.
    Llovet JM, Bruix J (2009) Testing molecular therapies in hepatocellular carcinoma: the need for randomized Phase II trials. J Clin Oncol 27:833–835CrossRefPubMedGoogle Scholar
  4. 4.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  5. 5.
    Chen TM, Chang TM, Huang PT, Tsai MH, Lin LF, Liu CC, Ho KS et al (2008) Management and patient survival in hepatocellular carcinoma: does the physician’s level of experience matter? J Gastroenterol Hepatol 23(7 Pt 2):e179–188Google Scholar
  6. 6.
    Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T et al (2008) Final results from a phase II (PhII), randomized, double-blind study of sorafenib plus doxorubicin (S+D) versus placebo plus doxorubicin (P+D) in patients (pts) with advanced hepatocellular carcinoma (AHCC). Gastrointestinal Cancer Symposium, Orlando, FL [Abstract 128]
  7. 7.
    Abou-Alfa GK, Zhao B, Capanu M, Guo P, Liu F, Jacobs G et al (2008) Tumor necrosis as a correlate for response in subgroup of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Ann Oncol 19(Suppl 8):viii178 [Abstract]Google Scholar
  8. 8.
    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 66:11851–11858CrossRefPubMedGoogle Scholar
  9. 9.
    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 23:965–972CrossRefPubMedGoogle Scholar
  10. 10.
    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 24:4293–4300CrossRefPubMedGoogle Scholar
  11. 11.
    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 10:25–34CrossRefPubMedGoogle Scholar
  12. 12.
    Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM et al (2001) Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg 233:227–235CrossRefPubMedGoogle Scholar
  13. 13.
    Lee TK, Poon RT, Yuen AP, Man K, Yang ZF, Guan XY et al (2006) Rac activation is associated with hepatocellular carcinoma metastasis by up-regulation of vascular endothelial growth factor expression. Clin Cancer Res 12:5082–5089CrossRefPubMedGoogle Scholar
  14. 14.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL et al (2003). A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody for metastatic renal cancer. N Engl J Med 349:427–434CrossRefPubMedGoogle Scholar
  15. 15.
    Malka D, Dromain C, Farace F, Horn S, Pignon J, Ducreux M 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 25(Suppl 18S):4570Google Scholar
  16. 16.
    Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ et al (2008) Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 262:992–998Google Scholar
  17. 17.
    Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5:203–220CrossRefPubMedGoogle Scholar
  18. 18.
    Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E et al (2009) Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 27:833–835CrossRefGoogle Scholar
  19. 19.
    Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337PubMedGoogle Scholar
  20. 20.
    Faivre SJ, Raymond E, Douillard J, Boucher E, Lim HY, Kim JS et al (2007) Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 25(Suppl 18S):3546Google Scholar
  21. 21.
    Zhu AX, Sahani DV, di Tomaso E, Duda DG, Catalano OA, Ancukiewicz M et al (2008) Sunitinib monotherapy in patients with advanced hepatocellular carcinoma (HCC): insights from a multidisciplinary phase II study. J Clin Oncol 26 (Suppl 15S):4521 [Abstract]Google Scholar
  22. 22.
    Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN et al (2008) Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 14:6146–6153CrossRefPubMedGoogle Scholar
  23. 23.
    Raoul JL, Finn RS, Kang YK, Park JW, Harris R, Coric V, 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 27:15 s [suppl; abstr 4577]Google Scholar
  24. 24.
    Finn RS, Kang Y, Park J, Harris R, Donica M, Walters I (2009) Phase II, open label study of brivanib alaninate in patients (pts) with hepatocellular carcinoma (HCC) who failed prior antiangiogenic therapy. Gastrointestinal Cancer Symposium, San Francisco, CA [Abstract No 200]Google Scholar
  25. 25.
    O’Dwyer PJ, Giantonio BJ, Levy DE, Kauh JS, Fitzgerald DB, Benson AB (2006) Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s Study E1203. J Clin Oncol 24(Suppl, 18S):4143Google Scholar
  26. 26.
    Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, et al. (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64(4):777–783Google Scholar
  27. 27.
    Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW et al (2007) Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110:581–589CrossRefPubMedGoogle Scholar
  28. 28.
    Gruenwald V, Wilkens L, Gebel M, Greten TF, Kubicka S, Ganser A,Manns MP, Malek NP (2007) A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: final results. J Clin Oncol 25(Suppl 18S):4598Google Scholar
  29. 29.
    Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G et al (2005) Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23:6657–6663CrossRefPubMedGoogle Scholar
  30. 30.
    Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T et al (2007) Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 110:1059–1067CrossRefPubMedGoogle Scholar
  31. 31.
    Llovet J, ASCO 2008, Chicago, IL [Commentary]Google Scholar
  32. 32.
    Huitzil FD, Saltz LS, Song J, Capanu M, Jacobs G, Moscovici M et al (2007) Retrospective analysis of outcome in hepatocellular carcinoma (HCC) patients (pts) with Hepatitis C (C+) versus B (B+) treated with Sorafenib (S). ASCO GI Oncology Symposium, Orlando, FL [Abstract 173]Google Scholar
  33. 33.
    Bolondi L, Caspary W, Bennouna J, Thomson B, Van Steenbergen WF et al (2008) Clinical benefit of sorafenib in hepatitis C patient with hepatocellular carcinoma (HCC): subgroup analysis of the SHARP trial. ASCO Gastrointestinal Cancer Symposium, Orlando, FL [Abstract 129]Google Scholar
  34. 34.
    Bürckstümmer T, Kriegs M, Lupberger J, Pauli EK, Schmittel S, Hildt E (2006) Raf-1 kinase associates with Hepatitis C virus NS5A and regulates viral replication. FEBS Lett 580:575–580CrossRefPubMedGoogle Scholar
  35. 35.
    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 20:2606–2610CrossRefPubMedGoogle Scholar
  36. 36.
    Kelley RK, Venook AP (2008) Sorafenib in hepatocellular carcinoma: separating the hype from the hope. J Clin Oncol 26:5845–5848CrossRefPubMedGoogle Scholar
  37. 37.
    Abou-Alfa GK, Amadori D, Santoro A, Figer A, De Greve J, Lathia C et al (2008) Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? J Clin Oncol 26(Suppl):4518 [Abstract]Google Scholar
  38. 38.
    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 99:159–165PubMedGoogle Scholar
  39. 39.
    Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa G et al (2009) Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27:1800–1805CrossRefPubMedGoogle Scholar
  40. 40.
    Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R et al (2009) Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 14:95–100CrossRefPubMedGoogle Scholar
  41. 41.
    Abou-Alfa GK (2009) Commentary: sorafenib – the end of a long journey in search of systemic therapy for hepatocellular carcinoma, or the beginning? Oncologist 14:92–94CrossRefPubMedGoogle Scholar
  42. 42.
    Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R et al (2009) Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 14:70–76CrossRefPubMedGoogle Scholar
  43. 43.
    Zhu AX, Clark JW (2009) Commentary: sorafenib use in patients with advanced hepatocellular carcinoma and underlying Child-Pugh B cirrhosis: evidence and controversy. Oncologist 14:67–69CrossRefPubMedGoogle Scholar
  44. 44.
    Cancer Care Ontario, Ontario, Canada, Accessed May 2009
  45. 45.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
  46. 46.
    Lamuraglia M, Escudier B, Chami L, Schwartz B, Leclère J, Roche A, Lassau N (2006) To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 42:2472–2479CrossRefPubMedGoogle Scholar
  47. 47.
    Benatsou B, Lassau N, Chami L, Koscielny S, Roche A, Ducreux M et al (2008) Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification for the early evaluation of hepato cellular carcinoma treated by bevacizumab in phase II. J Clin Oncol 26(Suppl):4588 [Abstract]Google Scholar
  48. 48.
    Sahani DV, Holalkere NS, Mueller PR, Zhu AX (2007) Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue–initial experience. Radiology 243:736–743CrossRefPubMedGoogle Scholar
  49. 49.
    Zhu AX, Holalkere NS, Muzikansky A, Horgan K, Sahani DV (2008) Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma. Oncologist 13:120–125CrossRefPubMedGoogle Scholar
  50. 50.
    Nussbaum T, Samarin J, Ehemann V, Bissinger M, Ryschich E, Khamidjanov A et al (2008) Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. Hepatology 48:146–156CrossRefPubMedGoogle Scholar
  51. 51.
    Tanaka S, Mori M, Sakamoto Y, Makuuchi M, Sugimachi K, Wands JR (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 103:341–345CrossRefPubMedGoogle Scholar
  52. 52.
    Hong D, Gordon M, Appleman L, Kurzrock R, Sun Y., Rasmussen E et al (2008) Interim results from a phase 1b study of safety, pharmacokinetics (PK) and tumor response of the angiopoietin1/2-neutralizing peptibody AMG 386 in combination with AMG 706, bevacizumab (b) or sorafenib (s) in advanced solid tumors. Ann Oncol 19(Suppl 8), viii154 [Abstract]Google Scholar
  53. 53.
    Huitzil FD, Sun MY, Capanu M, Blumgart LH, Jarnagin WR, Fong Y 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(Suppl 15S):4599 [Abstract]Google Scholar
  54. 54.
    Heideman DA, Overmeer RM, van Beusechem VW, Lamers WH, Hakvoort TB, Snijders PJ 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 12:954–962CrossRefPubMedGoogle Scholar
  55. 55.
    Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, Vivekanandan P et al (2006) Regulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748–757CrossRefPubMedGoogle Scholar
  56. 56.
    LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H et al. (2008) First-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. J Clin Oncol 26(Suppl 15S):3516 [Abstract]Google Scholar
  57. 57.

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jonas W. Feilchenfeldt
    • 1
  • Eileen M. O’Reilly
    • 1
  • Costantine Albany
    • 1
  • Ghassan K. Abou-Alfa
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations