Skip to main content

Advertisement

Log in

Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar®) was approved in Japan for “unresectable hepatocellular carcinoma (HCC)”, and was the first molecular-targeted agent for use in liver cancer. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and it has now been approved worldwide. Phase III clinical trials are now underway to compare other molecular-targeted agents with sorafenib as first-line treatment agents, and to evaluate other multi-kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptors, as well as drugs targeting the epidermal growth factor receptor, insulin-like growth factor receptor, and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687

    Article  CAS  PubMed  Google Scholar 

  2. Minguez B, Tovar V, Chiang D et al (2009) Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 25:186–194

    Article  CAS  PubMed  Google Scholar 

  3. Villanueva A, Newell P, Chiang DY et al (2007) Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27:55–76

    Article  CAS  PubMed  Google Scholar 

  4. Laurent-Puig P, Zucman-Rossi J (2006) Genetics of hepatocellular tumors. Oncogene 25:3778–3786

    Article  CAS  PubMed  Google Scholar 

  5. Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48:1312–1327

    Article  CAS  PubMed  Google Scholar 

  6. Hopfner M, Shuppan D, Scherubl H (2008) Growth factor receptors and related signaling pathways as target for novel treatment strategies of hepatocellular cancer. World J Gastroenterol 14:1–14

    Article  PubMed  Google Scholar 

  7. Campbell JS, Hughes SD, Gilbertson DG et al (2005) Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci 102:3389–3394

    Article  CAS  PubMed  Google Scholar 

  8. Ogasawara S, Yano H, Iemura A et al (1996) Expression of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines. Hepatology 24:198–205

    Article  CAS  PubMed  Google Scholar 

  9. Kudo M (2008) Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy. Oncology 75:S1–S12

    Article  Google Scholar 

  10. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    Article  CAS  PubMed  Google Scholar 

  11. Schmidt CM, McKillop IH, Cahill PA et al (1997) Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 236:54–58

    Article  CAS  PubMed  Google Scholar 

  12. Huynh H, Nguen TTT, Chow KHP et al (2003) Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterology 3:19–30

    Article  PubMed  Google Scholar 

  13. Calvisi DF, Ladu S, Gorden A et al (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117–1128

    Article  CAS  PubMed  Google Scholar 

  14. Bos JL (1989) ras Oncogenes in human cancer: review. Cancer Res 49:4682–4689

    CAS  PubMed  Google Scholar 

  15. Beeram M, Patnaik A, Rowinsky EK (2005) Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 23:6771–6790

    Article  CAS  PubMed  Google Scholar 

  16. Tannapfel A, Sommerer F, Benicke M et al (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712

    Article  CAS  PubMed  Google Scholar 

  17. Jenke HS, Deml E, Oesterle D (1994) C-raf expression in early ratliver tumorigenesis after promotion with polychlorinated biphenyls or Phenobarbital. Xenobiotica 24:569–580

    Article  CAS  PubMed  Google Scholar 

  18. Beer DG, Neveu MJ, Paul DL et al (1998) Expression of the c-raf protooncogene, gamma-glutamyltranspeptidase, and gap junction protein in rat liver neoplasms. Cancer Res 48:1610–1617

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Wilhelm SM, Adnane L, Newell P et al (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7:3129–3140

    Article  CAS  PubMed  Google Scholar 

  21. Ohren JF, Chen H, Pavlovsky A et al (2004) Structures of human MAP kinase kinase 1(MEK1) and MEK2 describe novel non competitive kinase inhibition. Nat Struct Mol Biol 11:1192–1197

    Article  CAS  PubMed  Google Scholar 

  22. Huynh H, Nguyen TTT, Chow KHP et al (2003) Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol 3:19–40

    Article  PubMed  Google Scholar 

  23. Engelma J (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  Google Scholar 

  24. Zhou L, Huang Y, Li J et al (2009) The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol (Epub ahead of print)

  25. Chen J, Wang Q, Fu X et al (2009) Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 39:177–186

    Article  CAS  PubMed  Google Scholar 

  26. Villanueva A, Chiang DY, Newell P et al (2008) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135:1972–1983

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  CAS  PubMed  Google Scholar 

  29. Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268

    CAS  PubMed  Google Scholar 

  30. Harper SJ, Bates DO (2008) VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 8:880–887

    Article  CAS  PubMed  Google Scholar 

  31. Fernandez M, Semela D, Bruix J et al (2009) Angiogenesis in liver disease. J Hepatol 50:604–620

    Article  CAS  PubMed  Google Scholar 

  32. Schoenleber SJ, Kurtzl DM, Talwalkar JA et al (2009) Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 100:1385–1392

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Zhu AX, Sahani DV, Duda DG et al (2009) Efficacy, safety, and potential biomarker of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035

    Article  CAS  PubMed  Google Scholar 

  35. Forner A, Llovet JM, Bruix J (2009) Sunitinib and the benefits of a negative study. Lancet Oncol 10:743–744

    Article  PubMed  Google Scholar 

  36. Raoul JL, Flinn 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

    Article  Google Scholar 

  37. Kanai F, Yoshida H, Tateishi R et al (2008) Final results of a phase I/II trial of the oral anti-angiogenesis inhibitor TSU-68 in patients with advanced hepatocellular carcinoma. J Clin Oncol 26 (abstract 4589)

  38. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

    Article  CAS  PubMed  Google Scholar 

  39. Buckley AF, Burgart LJ, Sahai V et al (2008) Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol 129:245–251

    Article  PubMed  Google Scholar 

  40. 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 23:6657–6663

    Article  CAS  PubMed  Google Scholar 

  41. Thomas MB, Chadhal R, Glover K et al (2007) Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 110:1059–1066

    Article  CAS  PubMed  Google Scholar 

  42. 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 27:843–850

    Article  CAS  PubMed  Google Scholar 

  43. Modified folfox7/bevacizumab or modified Xelox/bevacizumab with or without erlotinib in first-line metastatic colorectal cancer (MCRC): results of the feasibility phase of the DREAM-OPTIMOX3 study (GERCOR). J Clinical Oncol, 2007 ASCO Annual Meeting Proceedings Part I, vol 25, No. 18S: 4097

  44. Tournigand B, Samson W, Scheithauer C et al (2009) mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab alone or with erlotinib in first-line treatment of patients with metastatic colorectal cancer (mCRC): interim safety analysis of DREAM study. J Clin Oncol 27:15S, ASCO Annual Meeting Abstract No:4077C

  45. Hecht JR, Mitchell E, Chidiac T et al (2008) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Burris HA III, Hurwitz HI, Dees EC et al (2005) Phase I safety, pharmacokinetics, and clinical activity of Lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313

    Article  CAS  PubMed  Google Scholar 

  48. Bekaii-Saab T, Markowitz J, Prescott N et al (2009) A multi-institutional phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 15:5895–5901

    Article  CAS  PubMed  Google Scholar 

  49. Zhu AX, Stuart K, Blaszkowsky LS et al (2007) Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110:581–589

    Article  CAS  PubMed  Google Scholar 

  50. Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Dis 7:501–516

    Google Scholar 

  51. Scharf JG, Braulke T (2003) The role of the IGF axis in hepatocarcinogenesis. Horm Metab Res 35:685–693

    Article  CAS  PubMed  Google Scholar 

  52. Chen YW, Boyartchuk V, Lewis BC (2009) Differential roles of insulin-like growth factor receptor–and insulin receptor–mediated signaling in the phenotypes of hepatocellular carcinoma cells. Neoplasia 11:835–845

    CAS  PubMed  Google Scholar 

  53. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  CAS  PubMed  Google Scholar 

  54. 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 10:25–34

    Article  CAS  PubMed  Google Scholar 

  55. Kudo M (2010) Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma in Japan, including its impact on complete remission. Oncology (in press)

  56. Okita K, Imanaka K, Chiba N et al (2010) Phase III study of sorafenib in patients in Japan and Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization. ASCO Gastrointestinal Cancers Symposium Proceedings 2010: 89 (LBA128)

  57. Murata K, Suzuki H, Okano H et al (2010) Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma. Int J Clin Oncol 36:161–170

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Toh H, Chen PJ, 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)

    Article  Google Scholar 

  60. 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 26:2992–2998

    Article  CAS  PubMed  Google Scholar 

  61. O’Dwyer PJ, Giantonio 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 24:18S (Suppl, Abstr 4143)

    Article  Google Scholar 

  62. 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 64:777–783

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest statement

M. Kudo has received honoraria for the lecture from Bayer HealthCare, Pfizer, and Bristol-Meyers.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masatoshi Kudo.

About this article

Cite this article

Kudo, M. Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice. Int J Clin Oncol 15, 242–255 (2010). https://doi.org/10.1007/s10147-010-0089-y

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-010-0089-y

Keywords

Navigation