Abstract
A majority of patients with HCC present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. Systemic cytotoxic chemotherapy agents are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. Hepatocellular carcinomas are inherently chemotherapy-resistant tumors and are known to overexpress the multidrug resistance genes. Hepatocellular carcinoma is a very heterogeneous disease in terms of its etiology, molecular carcinogenic mechanisms, and biological behavior, which complicate our ability to identify rational molecular therapeutic “targets.” Nearly every pathway involved in carcinogenesis is altered to some degree in HCC. Changes in hepatocyte growth factor expression, intracellular signaling, protease and matrix metalloproteinase expression, and oncogene expression are seen in HCC. The recent demonstration, in randomized clinical trials, of survival benefit for HCC patients treated with the oral agent sorafenib is encouraging progress in the development of molecularly targeted anticancer agents in HCC.
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Simonetti RG, Liberati A, Angiolini C, et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol 1997;8:117–136.
Ng IO, Liu CL, Fan ST, et al. Expression of P-glycoprotein in hepatocellular carcinoma. A determinant of chemotherapy response. Am J Clin Pathol 2000;113:355–363.
Endicott JA, Ling V. The biochemistry of P-glycoproteinmediated drug resistance. Annu Rev Biochem 1989;58:137–171.
Park JG, Lee SK, Hong IG, et al. MDR1 gene expression: its effect on drug resistance to doxorubicin in human hepatocellular carcinoma cell lines. J Natl Cancer Inst 1994;86:700–705.
Tsang WP, Kwok TT. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 2007;26:4877–4881.
Chan KT, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol 2004;53:519–526.
Lasagna N, Fantappie O, Solazzo M, et al. Hepatocyte growth factor and inducible nitric oxide synthase are involved in multidrug resistance-induced angiogenesis in hepatocellular carcinoma cell lines. Cancer Res 2006;66:2673–2682.
Zhu H, Chen XP, Luo SF, et al. Involvement of hypoxia-inducible factor-1-alpha in multidrug resistance induced by hypoxia in HepG2 cells. J Exp Clin Cancer Res 2005;24:565–574.
Okada Y, Tosaka A, Nimura Y, et al. Atypical multidrug resistance may be associated with catalytically active mutants of human DNA topoisomerase II alpha. Gene (Amst) 2001;272:141–148.
Watanuki A, Ohwada S, Fukusato T, et al. Prognostic significance of DNA topoisomerase II alpha expression in human hepatocellular carcinoma. Anticancer Res 2002;22:1113–1119.
Hisaka T, Yano H, Haramaki M, et al. Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol 1999;14:453–460.
Fausto N. Growth factors in liver development, regeneration and carcinogenesis. Prog Growth Factor Res 1991;3:219–234.
Hopfner M, Sutter AP, Huether A, et al. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 41:1008–1016, 2004.
Huether A, Hopfner M, Sutter AP, et al. Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. J Hepatol 2005;43:661–669.
Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer (Phila) 2007;110:1059–1067.
Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657–6663.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.
Park YN, Kim YB, Yang KM, et al. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 2000;124:1061–1065.
Zhao J, Hu J, Cai J, et al. Vascular endothelial growth factor expression in serum of patients with hepatocellular carcinoma. Chin Med J (Engl) 2003;116:772–776.
Huang GW, Yang LY, Lu WQ. Expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor in hepatocellular carcinoma: impact on neovascularization and survival. World J Gastroenterol 2005;11:1705–1708.
Kanematsu M, Osada S, Amaoka N, et al. Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver: correlation with angiographically assisted CT. AJR Am J Roentgenol 2004;183:1585–1593.
Kanematsu M, Semelka RC, Osada S, et al. Magnetic resonance imaging and expression of vascular endothelial growth factor in hepatocellular nodules in cirrhosis and hepatocellular carcinomas. Top Magn Reson Imaging 2005;16:67–75.
Wang B, Gao ZQ, Yan X. Correlative study of angiogenesis and dynamic contrast-enhanced magnetic resonance imaging features of hepatocellular carcinoma. Acta Radiol 2005;46:353–358.
D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91:4082–4085.
Kenyon BM, Browne F, D’Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997;64:971–978.
Kumar S, Witzig TE, Rajkumar SV. Thalidomid: current role in the treatment of non-plasma cell malignancies. J Clin Oncol 2004;22:2477–2488.
Hsu C, Chen CN, Chen LT, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65:242–249.
Wang TE, Kao CR, Lin SC, et al. Salvage therapy for hepatocellular carcinoma with thalidomide. World J Gastroenterol 2004;10:649–653.
Lin AY, Brophy N, Fisher GA, et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer (Phila) 2005;103:119–125.
Patt YZ, Hassan MM, Lozano RD, et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer (Phila) 2005;103:749–755.
Schwartz JD, Sung M, Schwartz M, et al. Thalidomide in advanced hepatocellular carcinoma with optional low-dose interferonalpha2a upon progression. Oncologist 2005;10:718–727.
Zhu AX. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist 2006;11:790–800.
Zhu AX, Fuchs CS, Clark JW, et al. A phase II study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma. Oncologist 2005;10:392–398.
Fazio N, Petralia G, Mancuso P, et al. Thalidomide in patients with advanced hepatocellular carcinoma: a clinical/biological study. ASCO Annual Meeting Proceedings, Part I. J Clin Oncol 2007;25:A15076.
Zhu AX, Sahani DV, di Tomaso E, et al. A phase II study of sunitinib in patients with advanced hepatocellular carcinoma. ASCO Annual Meeting Proceedings, Part I. J Clin Oncol 2007:25:A4637.
Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:4293–4300.
Llovet J, Ricci S, et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a Phase III randomized placebo-controlled trial (SHARP trial). ASCO Annual Meeting Proceedings, Part I. J Clin Oncol 25:ABA1.
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987–989.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145–147.
Schwartz MS, Lehrer D, Cohen E, Sung M, Kinkhabwala M, Siegel A, et al. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. ASCO Annual Meeting Proceedings. J Clin Oncol 2006;24(18 suppl):A4144.
Malka D, Dromain C, Farace F, et al. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. ASCO Annual Proceedings, Part I. J Clin Oncol 2007;25:A4570.
Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898–1903.
Hsu C, Hsu C, Yang T, et al. Modified-dose capecitabine + bevacizumab for the treatment of advanced/metastatic hepatocellular carcinoma (HCC): a phase II, single-arm study. ASCO Annual Proceedings, Part I. J Clin Oncol 2007;25:A15190.
Sun W, Haller DG, Mykulowycz K, et al. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. ASCO Annual Proceedings, Part I. J Clin Oncol 2007;25:A4574.
Thomas MB, Chadha R, Iwasaki M, et al. The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma. ASCO Annual Proceedings, Part I. J Clin Oncol 2007;25:A4567.
Zhang Q, Tang X, Lu QY, et al. Resveratrol inhibits hypoxiainduced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Mol Cancer Ther 2005;4:1465–1474.
Okano H, Shiraki K, Yamanaka Y, et al. Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization. World J Gastroenterol 2005;11:4650–4654.
Toyoda M, Hashimoto N, Tokita K, et al. Increased activity and expression of MAP kinase in HCC model rats induced by 3′-methyl-4-dimethylamino-azobenzene. J Hepatol 1999;31:725–733.
McKillop IH, Schmidt CM, Cahill PA, et al. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 1997;26:1484–1491.
Ito Y, Sasaki Y, Horimoto M, et al. Activation of mitogenactivated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 1998;27:951–958.
Feng DY, Zheng H, Tan Y, et al. Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 2001;7:33–36.
Carloni V, Vizzutti F, Pantaleo P. Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Clin Cancer Res 2005;11:4266–4274.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390.
Alexia C, Bras M, Fallot G, et al. Pleiotropic effects of PI-3′ kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. Ann N Y Acad Sci 2006;1090:1–17.
Saxena NK, Sharma D, Ding X, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 2007;67:2497–2507.
Adjei AA, Hidalgo M. Treating cancer by blocking cell signals. J Clin Oncol 2005;23:5279–5280.
Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10:8421–8425.
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007;83:425–432.
Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005;97:1532–1538.
Mok TS, Leung TW, Lee SD, et al. A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 1999;44:307–311.
Posey JJP, Mok T, et al. Results of a phase 2/3 open-label, randomized trial of T138067 versus doxorubicin (DOX) in chemotherapy-naïve, unresectable hepatocellular carcinoma (HCC). J Clin Oncol 2005;23(suppl):4035.
Gish RG, Porta C, Lazar L, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 2007;25:3069–3075.
Pastorelli DCG, Zustovich F, et al. A phase II study of pegylated liposomial doxorubicin (PLD) and gemcitabine (G) in the treatment of hepatocellular carcinoma (HCC) not suitable for locoregional therapy. J Clin Oncol 2007;25(suppl):4585.
Thomas MBCR, Iwasaki M, et al. The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2007;25(suppl):4567.
Ramanathan CPB, Singh DA, et al. Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial. J Clin Oncol 2006;24(18 suppl):4010.
Gruenwald LW, Gebel M, et al. A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma. J Clin Oncol 2006;24(18 suppl):14079.
Zhu AXBL, Enzinger PC, et al. Phase II study of cetuximab in patients with unresectable or metastatic hepatocellular carcinoma. J Clin Oncol 2006;24(suppl):14096.
O’Dwyer PJGB, Levy DE, et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s Study E1203. J Clin Oncol 2006;24(suppl):4143.
Sun WHD, Mykulowycz K, et al. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. J Clin Oncol 2007;25(suppl):4574.
Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer (Phila) 2007;109:1384–1390.
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Thomas, M. Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol 44 (Suppl 19), 136–141 (2009). https://doi.org/10.1007/s00535-008-2252-z
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DOI: https://doi.org/10.1007/s00535-008-2252-z