Journal of Gastroenterology

, Volume 45, Issue 8, pp 794–807 | Cite as

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives



Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.


Hepatocellular carcinoma Molecular targeted therapy Anti-angiogenic therapy Sorafenib 


  1. 1.
    Llovet JM, Ricci S, Mazzaferro V, Hilgaard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Cheng AL, Kong YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Mise M, Arii S, Higashituji H, Furutani M, Niwano M, Harada T, et al. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology. 1996;23:455–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med. 2000;124:1061–5.PubMedGoogle Scholar
  5. 5.
    Li Q, Xu B, Fu L, Hao XS. Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2006;25:403–9.PubMedGoogle Scholar
  6. 6.
    Uematsu S, Higashi T, Nouso K, Kariyama K, Nakamura S, Suzuki M, et al. Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2005;20:583–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Li XM, Tang ZY, Zhou G, Lui YK, Ye SL. Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J Exp Clin Cancer. 1998;17:13–7.Google Scholar
  8. 8.
    Tsou AP, Wu KM, Tsen TY, Chi CW, Chiu JH, Lui WY, et al. Parallel hybridization analysis of multiple protein kinase: identification of gene expression patterns characteristic of human hepatocellular carcinoma. Genomics. 1998;50:331–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Stock P, Monga D, Tan X, Micsenyi A, Loizos N, Monga SP. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer. Mol Cancer Ther. 2007;6:1932–41.PubMedCrossRefGoogle Scholar
  10. 10.
    El-Assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N. The clinicopathological significance of heparanase and basic fibroblast growth factor expression in hepatocellular carcinoma. Clin Cancer Res. 2001;7:1299–305.PubMedGoogle Scholar
  11. 11.
    Tanaka S, Mori M, Sakamoto Y, Makuuchi M, Sugimachi K, Wands JR. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest. 1999;103:341–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Harada T, Arii S, Mise M, Imamura T, Higashitsuji H, Furutani M, et al. Membrane-type matrix metalloproteinase-1 (MT1-MMP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol. 1998;28:231–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Tshii Y, Nakasato Y, Kobayashi S, Yamazaki Y, Aoki T. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. J Exp Clin Cancer Res. 2003;22:461–70.Google Scholar
  14. 14.
    Dhar DK, Ono T, Yamanoi A, Soda Y, Yamaguchi E, Rahman MA, et al. Serum endostatin predicts tumor vascularity in hepatocellular carcinoma. Cancer. 2002;95:2188–95.PubMedCrossRefGoogle Scholar
  15. 15.
    Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Hicklin DJ, Ellis LM. Role of the vascular endothelial growth fator pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.PubMedCrossRefGoogle Scholar
  17. 17.
    Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90.PubMedCrossRefGoogle Scholar
  19. 19.
    Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Di Lorenzo G, Cartenì G, Autorino R, Bruni G, Tudini M, Rizzo M, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27:4469–74.PubMedCrossRefGoogle Scholar
  21. 21.
    Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist. 2007;12:356–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007;12:713–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28:2137–43.PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14:1131–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26:127–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Sherman M, Mazzaferro V, Amadori D, Seitz J, Moscovici M, Shan M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial. J Clin Oncol. 2008;26 (Suppl; abstract no. 4584).Google Scholar
  29. 29.
    Bolondi L, Caspary W, Bennouna J, Thomson B, Van Steenbergen W, Degos F, et al. Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): subgroup analysis of the SHARP trial. In: 2008 Gastrointestinal Cancers Symposium (abstract no. 129).Google Scholar
  30. 30.
    Raoul J, Santoro A, Beaugrand M, Marrero JA, Moscovici M, Shan M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial. J Clin Oncol. 2008;26 (Suppl; abstract no. 4587).Google Scholar
  31. 31.
    Craxi A, Porta C, Sangiovanni A, Seitz J, Moscovici M, Shan M, et al. Efficacy and safety of sorafenib in patients with alcohol-related hepatocellular carcinoma: a subanalysis from the SHARP trial. J Clin Oncol. 2008;26 (Suppl; abstract no. 15591).Google Scholar
  32. 32.
    Bruix J, Cheng A, Kang Y, Tsao C, Qin S, Lentini G, et al. Effect of macroscopic vascular invasion (MVI), extrahepatic spread (EHS), and ECOG performance status (ECOG PS) on outcome in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib: analysis of two phase III, randomized, double-blind trials. J Clin Oncol. 2009;27 (Suppl; abstract no. 4580).Google Scholar
  33. 33.
    Raoul J, Sherman M, Nadel A, Lentini G, Moscovici M, Voliotis D, et al. Efficacy and safety of sorafenib (Sor) in patients (pts) with advanced hepatocellular carcinoma (HCC): subgroup analyses of the SHARP trial by baseline (BL) transaminase (ALT/AST)/alphafetoprotein (AFP) and bilirubin (Bil) levels. In: 2010 Gastrointestinal Cancer Symposium (abstract no. 129).Google Scholar
  34. 34.
    Cantarini MC, Trevisani F, Morselli-Labate AM, Rapaccini G, Farinati F, Del Poggio P, et al. Effect of the etiology of viral cirrhosis on the survival of patients with hepatocellular carcinoma. Am J Gastroenterol. 2006;101:91–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Hsu C, Shen YC, Cheng CC, Hu FC, Cheng AL. Geographic difference in survival outcome for advanced hepatocellular carcinoma: Implications on future clinical trial design. Contemp Clin Trials. 2010;31:55–61.PubMedCrossRefGoogle Scholar
  36. 36.
    Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10:967–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Elbekai RH, Korashy HM, El-Kadi AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab. 2004;5:157–67.PubMedCrossRefGoogle Scholar
  38. 38.
    Frye RF, Zgheib NK, Matzke GR, Chaves-Gnecco D, Rabinovitz M, Shaikh OS, et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther. 2006;80:235–45.PubMedCrossRefGoogle Scholar
  39. 39.
    Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293–300.PubMedCrossRefGoogle Scholar
  40. 40.
    Furuse J, Ishii H, Nakachi K, Suzuki E, Shimizu S, Nakajima K. Phase I study of sorafenib in Japanese patients with heatocellular carcinoma. Cancer Sci. 2008;99:159–65.PubMedGoogle Scholar
  41. 41.
    Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa G, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009;14:70–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Wörns MA, Weinmann A, Pfingst K, Schulte-Sasse C, Messow CM, Schulze-Bergkamen H, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol. 2009;43:489–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Ozenne V, Paradis V, Pernot S, Castelnau V, Cullierme MP, Bouattour M, et al. Tolerance and outcome of patients with unresectable hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2010. [Epub ahead of print].Google Scholar
  45. 45.
    Faivre S, Demeri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6:734–45.PubMedCrossRefGoogle Scholar
  46. 46.
    Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol. 2009;10:794–800.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009;27:3027–35.PubMedCrossRefGoogle Scholar
  48. 48.
    Koeberle D, Montemurro M, Samaras P, Majno P, Simcock M, Limacher A, et al. Continuous sunitinib treatment in patients with advanced hepatocellular carcinoma: A Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). Oncologist. 2010;15:285–92.PubMedCrossRefGoogle Scholar
  49. 49.
    Raoul JL, Finn R, Kang YK, Park JW, Harris R, Coric V, et al. An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2009;27 (Suppl; abstract no. 4577).Google Scholar
  50. 50.
    Finn RS, Kang Y, Park J, Harris R, Donica M, Walters I. Phase II, open label study of brivanib alaninate in patients (pts) with hepatocellular carcinoma (HCC) who failed prior antiangiogenic therapy. In: 2009 Gastrointestinal Cancers Symposium. (abstract no. 200).Google Scholar
  51. 51.
    Finn RS, Park JW, Kang YK, et al. Time-to-progression sub-analysis of second-line treatment with brivanib after failure of prior antiangiogenic therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma. In: AASLD Annual Meeting 2009 (abstract).Google Scholar
  52. 52.
    Kanai F, Yoshida H, Teratani T, Sato S, Tateishi R, Obi S, et al. New feasibility study design with hepatocellular carcinoma: A phase I/II study of TSU-68, an oral angiogenesis inhibitor. J Clin Oncol. 2006;24 (Suppl; abstract no. 4145).Google Scholar
  53. 53.
    Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2010. [Epub ahead of print].Google Scholar
  54. 54.
    Toh H, Chen P, Carr BI, Knox JJ, Gill S, Qian J, et al. Linifanib phase II trial in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2010;28 (Suppl; abstract no. 4038).Google Scholar
  55. 55.
    Yau CC, Chen PJ, Curtis CM, Murphy PS, Suttle AB, Arumugham T, et al. A phase I study of pazopanib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:3561.Google Scholar
  56. 56.
    Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26:2992–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Bergers G, Hannahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.PubMedCrossRefGoogle Scholar
  58. 58.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.PubMedCrossRefGoogle Scholar
  59. 59.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalized tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95.PubMedCrossRefGoogle Scholar
  60. 60.
    Bertolini F, Mancuso P, Shaked Y, Kerbel RS. Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today. 2007;12:806–12.PubMedCrossRefGoogle Scholar
  61. 61.
    Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, et al. HIF 1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol. 2005;7:870–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comogli PM, et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncoene. Cancer Cell. 2003;3:347–61.PubMedCrossRefGoogle Scholar
  64. 64.
    Steeg PS. Angiogenesis inhibitors: motivators of metastasis? Nat Med. 2003;9:822–3.PubMedCrossRefGoogle Scholar
  65. 65.
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91:4082–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Kruse FE, Joussen AM, Rohrschneider K, Becker MD, Völcker HE. Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Opthalmol. 1998;236:461–6.CrossRefGoogle Scholar
  67. 67.
    Kumar S, Witzig TE, Rajkumar SV. Thalidomide: current role in the treatment of non-plasma cell malignancies. J Clin Oncol. 2004;22:2477–88.PubMedCrossRefGoogle Scholar
  68. 68.
    Hsu C, Chen CN, Chen LT, Wu CY, Hsieh FJ, Cheng AL. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology. 2003;65:242–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Patt YZ, Hassan MM, Lozano RD, Nooka AK, Schnirer II, Zeldis JB, et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer. 2005;103:749–55.PubMedCrossRefGoogle Scholar
  70. 70.
    Chiou HE, Wang TE, Wang YY, Liu HW. Efficacy and safety of thalidomide in patients with hepatocellular carcinoma. World J Gastroenterol. 2006;12:6955–6.PubMedGoogle Scholar
  71. 71.
    Chuah B, Lim R, Boyer M, Ong AB, Wong SW, Kong HL, Millward M, et al. Multi-centre phase II trial of thalidomide in the treatment of unresectable hepatocellular carcinoma. Acta Oncol. 2007;46:234–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Chen LT, Liu TW, Chao Y, Shiah HS, Chang JY, Juang SH, et al. Alpha-fetoprotein response predicts survival benefits of thalidomide in advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2005;22:217–26.PubMedCrossRefGoogle Scholar
  73. 73.
    Yau T, Chan P, Wong H, Ng KK, Chok SH, Cheung TT, et al. Efficacy and tolerability of low-dose thalidomide as first-line systemic treatment of patients with advanced hepatocellular carcinoma. Oncology. 2007;72:67–71.PubMedCrossRefGoogle Scholar
  74. 74.
    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–36.PubMedCrossRefGoogle Scholar
  75. 75.
    Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol. 2001;2:733–40.PubMedCrossRefGoogle Scholar
  76. 76.
    Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cyotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA. 2003;100:12917–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Sampson JH, Sathornsumetee S, et al. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer. 2009;101:1986–94.PubMedCrossRefGoogle Scholar
  79. 79.
    Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 2008;26:76–82.PubMedCrossRefGoogle Scholar
  80. 80.
    Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol. 2008;26:4899–905.PubMedCrossRefGoogle Scholar
  81. 81.
    Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, et al. Phase II study of combining sorafenbi with metronomic tegafur/uracil for advanced hepatocelular carcinoma. J Hepatol. 2010. doi: 10.1016/j.jhep.2010.01.035.
  82. 82.
    Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, et al. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer. 2010;102:981–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Hsu C, Chang D, Lin Z, Lee K, Hsiao C, Shen Y, et al. Thalidomide plus tegafur/uracil for the treatment of advanced/metastatic hepatocellular carcinoma (HCC): a phase II single-arm study. J Clin Oncol. 2008;26 (Suppl; abstract no. 15598).Google Scholar
  84. 84.
    Jeong W, Chun HG, Cer D, Sekhri V, Kim-Schluger L, Wolf D. A combination of capecitabine and thalidomide in patients with hepatocellular carcinoma. J Clin Oncol. 2006;24 (Suppl; abstract no. 4142).Google Scholar
  85. 85.
    Thomas MB, Abbruzzese JL. Opportunities for targeted therapies in hepatocellular carcinoma. J Clin Oncol. 2005;23:8093–108.PubMedCrossRefGoogle Scholar
  86. 86.
    Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis. 2010;30:35–51.PubMedCrossRefGoogle Scholar
  87. 87.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.PubMedCrossRefGoogle Scholar
  88. 88.
    Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology. 1998;27:951–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Huynh H, Nguyen TT, Chow KH, Tan PH, Soo KC, Tran E. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 2003;8:3–19.Google Scholar
  90. 90.
    Lee HC, Tian B, Sedivy JM, Wands JR, Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology. 2006;131:1208–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Erhardt A, Hassan M, Heintges T, Häussinger D. Hepatitis C virus core protein induces cell proliferation, activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line. Virology. 2002;292:272–84.PubMedCrossRefGoogle Scholar
  92. 92.
    Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J. 2004;18:1123–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706–12.PubMedCrossRefGoogle Scholar
  94. 94.
    O’Neil BH, Williams-Goff LW, Kauh J, Bekaii-Saab T, Strosberg JR, Lee R, et al. A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma. J Clin Oncol. 2009;27:15574.Google Scholar
  95. 95.
    Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335–48.PubMedCrossRefGoogle Scholar
  96. 96.
    Fujiwara Y, Hoon DS, Yamada T, Umeshita K, Gotoh M, Sakon M, et al. PTEN/MMAC1 mutation and frequent loss of heterozygosity identified in chromosome 10q in a subset of hepatocellular carcinoma. Jpn J Cancer Res. 2000;92:287–92.Google Scholar
  97. 97.
    Hu TH, Huang CC, Lin PR, Lin PR, Liu SY, Chang HW, et al. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer. 2003;97:1929–40.PubMedCrossRefGoogle Scholar
  98. 98.
    Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972–83.PubMedCrossRefGoogle Scholar
  99. 99.
    Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004;10:8421–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Chen KF, Yeh PY, Yeh KH, Lu YS, Huang SY, Cheng AL. Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 2008;68:6698–707.PubMedCrossRefGoogle Scholar
  101. 101.
    Chen KF, Yeh PY, Hsu C, Hsu CH, Lu YS, Hsieh HP, et al. Bortezoomib overcomes tumor necorsis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells in part through the inhibition of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2009;284:11121–33.PubMedCrossRefGoogle Scholar
  102. 102.
    Rizell M, Andersson M, Cahlin C, Hafström L, Olausson M, Lindnér P. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol. 2008;13:66–70.PubMedCrossRefGoogle Scholar
  103. 103.
    Chen L, Shiah HS, Chen CY, Lin YJ, Lin PW, Su WC, Chan JY. Randomized, phase I, and pharmacokinetic (PK) study of RAD001, an mTOR inhibitor, in patients (pts) with advanced hepatocelluar carcinoma (HCC). J Clin Oncol 2009;27 (Suppl; abstract no. 4587).Google Scholar
  104. 104.
    Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25:3787–800.PubMedCrossRefGoogle Scholar
  105. 105.
    Furuse J. Growth factors as therapeutic targets in HCC. Crit Rev Oncol Hematol. 2008;67:8–15.PubMedCrossRefGoogle Scholar
  106. 106.
    Hamazaki K, Yunoki Y, Tagashira H, Mimura T, Mori M, Orita K. Epidermal growth factor receptor in human hepatocellular carcinoma. Cancer Detect Prev. 1997;21:355–60.PubMedGoogle Scholar
  107. 107.
    Altimari A, Fiorentino M, Gabusi E, Gruppioni E, Corti B, D’Errico A, Grigioni WF. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours. Dig Liver Dis. 2003;35:332–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Hsu C, Huang CL, Hsu HC, Lee PH, Wang SJ, Cheng AL. HER-2/neu overexpression is rare in hepatocellular carcinoma and not predictive of anti-HER-2/neu regulation of cell growth and chemosensitivity. Cancer. 2002;94:415–20.PubMedCrossRefGoogle Scholar
  109. 109.
    Su MC, Lien HC, Jeng YM. Absence of epidermal growth factor receptor exon 18–21 mutation in hepatocellular carcioma. Cancer Lett. 2005;224:117–21.PubMedGoogle Scholar
  110. 110.
    Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23:6657–63.PubMedCrossRefGoogle Scholar
  111. 111.
    Thomas MB, Ghadha R, Glover K, Wang X, Morris J, Brown T, et al. Phase II study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;110:1059–67.PubMedCrossRefGoogle Scholar
  112. 112.
    O’Dwyer PJ, Gianotonio BJ, Levy DE, Kauh JS, Fitzgerald DB, Benson AB. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s Study E1203. J Clin Oncol. 2006;24 (Suppl; abstract no. 4143).Google Scholar
  113. 113.
    Bekaii-Saab T, Markowitz J, Prescott N, Sadee W, Heerema N, Wei L, et al. A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res. 2009;15:5895–901.PubMedCrossRefGoogle Scholar
  114. 114.
    Gruenwald V, Wilkens L, Gebel M, Wirth T, Greten S, Kubicka MP, et al. A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma. J Clin Oncol. 2006;24:14079.Google Scholar
  115. 115.
    Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW, et al. Phase 2 study of cetuximab in patients with advanced HCC. Cancer. 2007;110:581–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Scharf JG, Dombrowski F, Ramadori G. The IGF axis and hepatocarcinogenesis. Mol Pathol. 2001;54:138–44.PubMedCrossRefGoogle Scholar
  117. 117.
    Aishima S, Basaki Y, Oda Y, Kuroda Y, Nishihara Y, Taguchi K, et al. High expression of insulin-like growth factor binding protein-3 is correlated with low portal invasion and better prognosis in human hepatocellular carcinoma. Cancer Sci. 2006;97:1182–90.PubMedCrossRefGoogle Scholar
  118. 118.
    Breuhahn K, Schirmacher P. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J Gastroenterol. 2008;14:1690–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Sole M, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol. 2010;52:550–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Okano J, Shiota G, Kawasaki H. Expression of hepatocyte growth factor (HGF) and HGF receptor (c-met) proteins in liver disease: an immunohistochemical study. Liver. 1999;19:151–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Osada S, Kanematsu M, Imai H, Goshima S. Clinical significance of serum HGF and c-Met expression in tumor tissue for evaluation of properties and treatment of hepatocellular carcinoma. Hepatogastroenterology. 2008;55:544–9.PubMedGoogle Scholar
  122. 122.
    Chiba T, Yokosuka O, Arai M, Tada M, Fukai K, Imazeli E, et al. Identification of genes up-regulated by histone deaceetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells. J Hepatol. 2004;41:436–45.PubMedCrossRefGoogle Scholar
  123. 123.
    Yamashita Y, Shimada M, Harimoto N, Rikimaru T, Shirabe K, Tanaka S, et al. Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells. In J Cancer. 2003;103:572–6.Google Scholar
  124. 124.
    Lu YS, Kashida Y, Kulp SK, Wang YC, Wnag D, Hung JH, et al. Efficay of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma. Hepatology. 2007;46:1119–30.PubMedCrossRefGoogle Scholar
  125. 125.
    Shirakawa H, Suzuki H, Shimomura M, Kojima M, Gotohda N, Takahashi S, et al. Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci. 2009;100:1403–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Baumhoer D, Tornillo L, Stadimann S, Roncalli M, Diamantis EK, Terracciano LM. Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples. Am J Clin Pathol. 2008;29:1319–26.Google Scholar
  127. 127.
    Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol. 2009;51:725–33.PubMedCrossRefGoogle Scholar
  128. 128.
    Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med. 2009;13:2673–83.PubMedCrossRefGoogle Scholar
  129. 129.
    Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, Fartoux L, Venot C, Bladt F, et al. 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. 2009;15:5445–56.PubMedCrossRefGoogle Scholar
  130. 130.
    Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, Barbu V, Fartoux L, Poupon R, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer. 2006;119:2557–66.PubMedCrossRefGoogle Scholar
  131. 131.
    Ou DL, Shen YC, Liang JD, Liou JY, Yu SL, Fan HH, et al. Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signaling-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma. Clin Cancer Res. 2009;15:5820–8.PubMedCrossRefGoogle Scholar
  132. 132.
    Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:843–50.PubMedCrossRefGoogle Scholar
  133. 133.
    Kaseb AL, Iwasaki M, Javle M, Onicescu G, Garrett-Mayer E, Abbruzzese GL, et al. Biological activity of bevacizumab and erlotinib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2009;27 (Suppl; abstract no. 4522).Google Scholar
  134. 134.
    Govindarajan R, Siegel ER, Makhoul I, Williamson SK. Phase II study of efficacy of bevacizumab and erlotinib in inoperable previously untreated hepatocellular carcinoma (HCC). In: 2009 Gastrointestinal Cancers Symposium (abstract no. 264).Google Scholar
  135. 135.
    Hsu C, Kang Y, Yang T, Su W, Sandoval-Tan J, Chiou T, et al. A phase II study of bevacizumab (B) and erlotinib (E) in combination for Asian patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC): an interim report. J Clin Oncol. 2009;27 (Suppl; abstract no. 4585).Google Scholar
  136. 136.
    Hsu C, Yang TS, Huo TI, Hsieh RK, Hwang WS, Hsieh TY, et al. Evaluation of vandetanib in patients with inoperable hepatocellular carcinoma (HCC): a randomized, double-blind, parallel group, multicenter, Phase II study. European Cancer Organization (ECCO) 15/European Society of Medical Oncology (ESMO) 34 Meeting, 2009 (abstract no. 6518).Google Scholar
  137. 137.
    Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605–11.PubMedCrossRefGoogle Scholar
  138. 138.
    Pitini V, Sturniolo G, Arrigo C, Leonardi S, Pino S, Altavilla G. HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy. Br J Haematol. 2010. [Epub ahead of print].Google Scholar
  139. 139.
    Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis. 2010;30:61–74.PubMedCrossRefGoogle Scholar
  140. 140.
    Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Kokudo N, Makuuchi M. Evidence-based clinical practice guidelines for hepatocellular carcinoma in Japan: the J-HCC guidelines. J Gastroenterol. 2009;44:119–21.PubMedCrossRefGoogle Scholar
  142. 142.
    Kudo M, Okanoue T. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology. 2007;72:2–15.PubMedCrossRefGoogle Scholar
  143. 143.
    Poon RT, Fan ST. Hepatectomy for hepatocellular carcinoma: patient selection and postoperative outcome. Liver Transpl. 2004;10:S39–45.PubMedCrossRefGoogle Scholar
  144. 144.
    Shao YY, Lin ZZ, Chen TJ, Hsu C, Shen YC, Hsu CH, Cheng AL. Prognostic values of baseline circulating endothelial progenitor level for advanced heaptocellular carcinoma (HCC) patients under anti-angiogenic therapy. J Clin Oncol. 2010;28 (abstract).Google Scholar
  145. 145.
    Booiege V, Baey C, Dromain C, Ducreux M, Malka D, Pignon J, et al. Circulating endothelial cells (CEC) and angiogenic proteins monitoring in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. J Clin Oncol. 2009;27 (Suppl; abstract no. 4597).Google Scholar
  146. 146.
    Sessa C, Guibal A, Del Conte G, Ruegg C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Rev Pract Oncol. 2008;5:378–91.CrossRefGoogle Scholar
  147. 147.
    Murukesh N, Dive C, Jayson GC. Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer. 2010;102:8–18.PubMedCrossRefGoogle Scholar
  148. 148.
    O’Connor JPB, Jackson A, Parker GJM, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer. 2007;96:189–95.PubMedCrossRefGoogle Scholar
  149. 149.
    Leach MO, Brindle KM, Evelhock JL, Griffiths JR, Horsman MR, Jackson A, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer. 2005;92:1599–610.PubMedCrossRefGoogle Scholar
  150. 150.
    Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JX, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6:327–38.PubMedCrossRefGoogle Scholar
  151. 151.
    Shen YC, Hsu CY, Yu CW, Hsu C, Hsu CH, Cheng AL, et al. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict treatment outcomes for advanced hepatocellular carcinoma (HCC) patients who received sorafenib plus tegafur/uracil therapy. J Hepatol. 2010;52 (Suppl 1):S52 (abstract no. 116).Google Scholar
  152. 152.
    Mirlacher M, Kasper M, Storz M, Knecht Y, Dürmüller U, Simon R, et al. Influence of slide aging on results of translational research studies using immunohistochemistry. Mod Pathol. 2004;17:1414–20.PubMedCrossRefGoogle Scholar
  153. 153.
    Shao YY, Chen CL, Huang CC, Tu HC, Lin ZZ, Hsu CH, et al. Discordance of the immunohistochemical expression of phosphor-Akt and phosphor-ERK between paired biopsy and hepatectomy specimens of hepatocellular carcinoma. In: AACR annual meeting 2010 (Abstract no. 3759).Google Scholar
  154. 154.
    Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.PubMedCrossRefGoogle Scholar
  155. 155.
    Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, et al. Gene expression patterns in human liver cancers. Mol Biol Cell. 2002;13:1929–39.PubMedCrossRefGoogle Scholar
  156. 156.
    Izuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–9.CrossRefGoogle Scholar
  157. 157.
    Breuhahan K, Vreden S, Haddad R, Beckebaum S, Stippel D, Flemming P, et al. Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression. Cancer Res. 2004;64:6058–64.CrossRefGoogle Scholar
  158. 158.
    Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellulr carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.PubMedCrossRefGoogle Scholar
  159. 159.
    Midorkawa Y, Tsutsumi S, Nishimura K, Kamimura N, Kano M, Sakamoto H, et al. Distinct chromosomal bias of gene expression signatures in the progression of hepatocellular carcinoma. Cancer Res. 2004;64:7263–70.CrossRefGoogle Scholar
  160. 160.
    Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.PubMedCrossRefGoogle Scholar
  161. 161.
    Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68:6779–88.PubMedCrossRefGoogle Scholar
  162. 162.
    Dalton WS, Friend SH. Cancer biomarkers––an invitation to the table. Science. 2006;312:1165–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Dash A, Maine IP, Varambally S, Shen R, Chinnaiyan AM, Rubin MA. Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens. Am J Pathol. 2002;161:1743–8.PubMedGoogle Scholar
  164. 164.
    El-Serag HB, Nurgalieva ZZ, Mistretta TA, Finegold MJ, Souza R, Hilsenbeck S, et al. Gene expression in Barrett’s esophagus: laser capture versus whole tissue. Scand J Gastroenterol. 2009;44:787–95.PubMedCrossRefGoogle Scholar
  165. 165.
    Klee EW, Erdogan S, Tillmans L, Kosari F, Sun Z, Wigle DA. Impact of sample acquisition and linear amplification on gene expression profiling of lung adenocarcinoma: laser capure micro-dissection cell-sampling versus bulk tissue-sampling. BMC Med Genom. 2009;9:2–13.Google Scholar
  166. 166.
    De Cecco L, Musella V, Veneroni S, Cappelletti V, Bongarzone I, Callari M, et al. Impact of biospecimens handling on biomarker research in breast cancer. BMC Cancer. 2009;9:409–10.PubMedCrossRefGoogle Scholar
  167. 167.
    Hoshida Y, Nijman SMB, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–92.PubMedCrossRefGoogle Scholar
  168. 168.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–42.PubMedCrossRefGoogle Scholar
  169. 169.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.PubMedCrossRefGoogle Scholar
  170. 170.
    Demetri GD. Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development. Hematol Oncol Clin North Am. 2002;16:1115–24.PubMedCrossRefGoogle Scholar
  171. 171.
    Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006;9:485–95.PubMedCrossRefGoogle Scholar
  172. 172.
    Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res. 2006;12:6326–30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Ying-Chun Shen
    • 1
    • 2
    • 3
  • Chiun Hsu
    • 1
    • 3
    • 4
  • Ann-Lii Cheng
    • 1
    • 3
    • 4
    • 5
  1. 1.National Center of Excellence for Clinical Trial and ResearchNational Taiwan University HospitalTaipeiTaiwan
  2. 2.Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
  4. 4.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  5. 5.Graduate Institute of Oncology, College of MedicineNational Taiwan UniversityTaipeiTaiwan

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