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The Future Prospect of Targeted Therapy in Hepatocellular Carcinoma

  • Stephanie H. Greco
  • Kristen Spencer
  • Darren R. CarpizoEmail author
Chapter
Part of the Molecular Pathology Library book series (MPLB)

Abstract

Liver cancer is the sixth most common cancer and the second leading cause of death worldwide. Only 30–40% of patients are candidates for curative intervention at the time of diagnosis, and up to 70% of those who undergo curative resection will recur. Cytotoxic chemotherapy in advanced disease is not effective and is often limited by concomitant hepatic dysfunction. Sorafenib, a multiple kinase inhibitor, is the only therapy to have shown an overall survival benefit that is only modest at best. Thus, there is a large unmet need to develop additional therapies. In recent years, a diverse array of phenotypic and genetic alterations have been identified in HCC patients. Following these advances, several phase III studies with therapies targeted toward these alterations have been conducted; however, none has shown a survival benefit. It remains to be seen if this new understanding in these alterations can be translated therapeutically. In this chapter, we will discuss these alterations, as well as the developing therapies targeting them.

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.PubMedCrossRefGoogle Scholar
  2. 2.
    Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42(Suppl 3):S206–14.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.PubMedCrossRefGoogle Scholar
  4. 4.
    Shah SA, Cleary SP, Wei AC, et al. Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery. 2007;141:330–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Huang C, Xu D, Xia Q, et al. Reversal of P-glycoprotein-mediated multidrug resistance of human hepatic cancer cells by Astragaloside II. J Pharm Pharmacol. 2012;64:1741–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Chan KT, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 2004;53:519–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang C, Zhang Y, Guo K, et al. Heat shock proteins in hepatocellular carcinoma: molecular mechanism and therapeutic potential. Int J Cancer. 2016;138:1824–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Wen L, Liang C, Chen E, et al. Regulation of multi-drug resistance in hepatocellular carcinoma cells is TRPC6/calcium dependent. Sci Rep. 2016;6:23269.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Deng GL, Zeng S, Shen H. Chemotherapy and target therapy for hepatocellular carcinoma: new advances and challenges. World J Hepatol. 2015;7:787–98.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Nagahama H, Okada S, Okusaka T, et al. Predictive factors for tumor response to systemic chemotherapy in patients with hepatocellular carcinoma. Jpn J Clin Oncol. 1997;27:321–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Olweny CL, Toya T, Katongole-Mbidde E, et al. Treatment of hepatocellular carcinoma with adriamycin. Preliminary communication. Cancer. 1975;36:1250–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Chlebowski RT, Brzechwa-Adjukiewicz A, Cowden A, et al. Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results. Cancer Treat Rep. 1984;68:487–91.PubMedGoogle Scholar
  14. 14.
    Choi TK, Lee NW, Wong J. Chemotherapy for advanced hepatocellular carcinoma. Adriamycin versus quadruple chemotherapy. Cancer. 1984;53:401–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Ihde DC, Kane RC, Cohen MH, et al. Adriamycin therapy in American patients with hepatocellular carcinoma. Cancer Treat Rep. 1977;61:1385–7.PubMedGoogle Scholar
  16. 16.
    Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev. 1988;15:1–31.PubMedCrossRefGoogle Scholar
  17. 17.
    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;97:1532–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Lai CL, PC W, Chan GC, et al. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62:479–83.PubMedCrossRefGoogle Scholar
  19. 19.
    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;25:3069–75.PubMedCrossRefGoogle Scholar
  20. 20.
    Sciarrino E, Simonetti RG, Le Moli S, et al. Adriamycin treatment for hepatocellular carcinoma. Experience with 109 patients. Cancer. 1985;56:2751–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Boige V, Taieb J, Hebbar M, et al. Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter phase II study with dose adjustment according to baseline serum bilirubin level. Eur J Cancer. 2006;42:456–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Dunk AA, Scott SC, Johnson PJ, et al. Mitozantrone as single agent therapy in hepatocellular carcinoma. A phase II study. J Hepatol. 1985;1:395–404.PubMedCrossRefGoogle Scholar
  23. 23.
    Halm U, Etzrodt G, Schiefke I, et al. A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma. Ann Oncol. 2000;11:113–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Kubicka S, Rudolph KL, Tietze MK, et al. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepato-Gastroenterology. 2001;48:783–9.PubMedGoogle Scholar
  25. 25.
    Lin AY, Brophy N, Fisher GA, et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer. 2005;103:119–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Pohl J, Zuna I, Stremmel W, et al. Systemic chemotherapy with epirubicin for treatment of advanced or multifocal hepatocellular carcinoma. Chemotherapy. 2001;47:359–65.PubMedCrossRefGoogle Scholar
  27. 27.
    Porta C, Moroni M, Nastasi G, et al. 5-Fluorouracil and d,l-leucovorin calcium are active to treat unresectable hepatocellular carcinoma patients: preliminary results of a phase II study. Oncology. 1995;52:487–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Tetef M, Doroshow J, Akman S, et al. 5-fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial. Cancer Investig. 1995;13:460–3.CrossRefGoogle Scholar
  29. 29.
    Brandi G, De Rosa F, Agostini V, et al. Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study. Oncologist. 2013;18:1256–7.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004;101:578–86.PubMedCrossRefGoogle Scholar
  31. 31.
    Abdel-Rahman O, Abdel-Wahab M, Shaker M, et al. Sorafenib versus capecitabine in the management of advanced hepatocellular carcinoma. Med Oncol. 2013;30:655.PubMedCrossRefGoogle Scholar
  32. 32.
    Parikh PM, Fuloria J, Babu G, et al. A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma. Trop Gastroenterol. 2005;26:115–8.PubMedGoogle Scholar
  33. 33.
    Lombardi G, Zustovich F, Farinati F, et al. Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma: results of a phase 2 study. Cancer. 2011;117:125–33.PubMedCrossRefGoogle Scholar
  34. 34.
    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. 2007;109:1384–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Boige V, Raoul JL, Pignon JP, et al. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007;97:862–7.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31:3501–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Leung TW, Patt YZ, Lau WY, et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res. 1999;5:1676–81.PubMedGoogle Scholar
  38. 38.
    Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.PubMedCrossRefGoogle Scholar
  39. 39.
    Farazi PA, Depinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.PubMedCrossRefGoogle Scholar
  40. 40.
    Yin C, Evason KJ, Asahina K, et al. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 2013;123:1902–10.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ahn SM, Jang SJ, Shim JH, et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology. 2014;60:1972–82.PubMedCrossRefGoogle Scholar
  42. 42.
    Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kan Z, Zheng H, Liu X, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–33.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Llovet JM, Villanueva A, Lachenmayer A, et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12:436.PubMedCrossRefGoogle Scholar
  45. 45.
    Villanueva A, Llovet JM. Liver cancer in 2013: mutational landscape of HCC—the end of the beginning. Nat Rev Clin Oncol. 2014;11:73–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Schulze K, Imbeaud S, Letouze E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68:6779–88.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Sawey ET, Chanrion M, Cai C, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell. 2011;19:347–58.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–73.PubMedCrossRefGoogle Scholar
  50. 50.
    Kramer OH. HDAC2: a critical factor in health and disease. Trends Pharmacol Sci. 2009;30:647–55.PubMedCrossRefGoogle Scholar
  51. 51.
    Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.PubMedCrossRefGoogle Scholar
  52. 52.
    Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Res. 2016;5:879.CrossRefGoogle Scholar
  53. 53.
    Gouas DA, Shi H, Hautefeuille AH, et al. Effects of the TP53 p.R249S mutant on proliferation and clonogenic properties in human hepatocellular carcinoma cell lines: interaction with hepatitis B virus X protein. Carcinogenesis. 2010;31:1475–82.PubMedCrossRefGoogle Scholar
  54. 54.
    Hamid AS, Tesfamariam IG, Zhang Y, et al. Aflatoxin B1-induced hepatocellular carcinoma in developing countries: geographical distribution, mechanism of action and prevention. Oncol Lett. 2013;5:1087–92.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet. 1991;338:1356–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Lunn RM, Zhang YJ, Wang LY, et al. p53 mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res. 1997;57:3471–7.PubMedGoogle Scholar
  57. 57.
    Kasprzak A, Adamek A, Przybyszewska W, et al. p53 immunocytochemistry and TP53 gene mutations in patients with chronic hepatitis C virus (HCV) infection. Folia Histochem Cytobiol. 2009;47:35–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Liu J, Ma Q, Zhang M, et al. Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer. 2012;48:2328–38.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Lachenmayer A, Alsinet C, Savic R, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 2012;18:4997–5007.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Llovet JM, Chen Y, Wurmbach E, et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology. 2006;131:1758–67.PubMedCrossRefGoogle Scholar
  62. 62.
    Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 2007;46:590–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Luedde T, Schwabe RF. NF-kappaB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8:108–18.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Matter MS, Decaens T, Andersen JB, et al. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol. 2014;60:855–65.PubMedCrossRefGoogle Scholar
  65. 65.
    Llovet JM, Villanueva A, Lachenmayer A, et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12:408–24.PubMedCrossRefGoogle Scholar
  66. 66.
    Baba HA, Wohlschlaeger J, Cicinnati VR, et al. Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma. Liver Int. 2009;29:399–405.PubMedCrossRefGoogle Scholar
  67. 67.
    Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972–1983, 1983 e1–11.Google Scholar
  68. 68.
    Zhou L, Huang Y, Li J, et al. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol. 2010;27:255–61.PubMedCrossRefGoogle Scholar
  69. 69.
    Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130:1117–28.PubMedCrossRefGoogle Scholar
  70. 70.
    Newell P, Toffanin S, Villanueva A, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Delire B, Starkel P. The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur J Clin Investig. 2015;45:609–23.CrossRefGoogle Scholar
  72. 72.
    Nakamura H, Aoki H, Hino O, et al. HCV core protein promotes heparin binding EGF-like growth factor expression and activates Akt. Hepatol Res. 2011;41:455–62.PubMedCrossRefGoogle Scholar
  73. 73.
    Zhang X, Zhang H, Ye L. Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med. 2006;147:58–66.PubMedCrossRefGoogle Scholar
  74. 74.
    Chen L, Shi Y, Jiang CY, et al. Expression and prognostic role of pan-Ras, Raf-1, pMEK1 and pERK1/2 in patients with hepatocellular carcinoma. Eur J Surg Oncol. 2011;37:513–20.PubMedCrossRefGoogle Scholar
  75. 75.
    Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2014;60:885–90.PubMedCrossRefGoogle Scholar
  76. 76.
    Villanueva A, Alsinet C, Yanger K, et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012;143:1660.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–9.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lachenmayer A, Toffanin S, Cabellos L, et al. Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib. J Hepatol. 2012;56:1343–50.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Witt O, Lindemann R. HDAC inhibitors: magic bullets, dirty drugs or just another targeted therapy. Cancer Lett. 2009;280:123–4.PubMedCrossRefGoogle Scholar
  80. 80.
    Khan O, La Thangue NB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 2012;90:85–94.PubMedCrossRefGoogle Scholar
  81. 81.
    LM W, Yang Z, Zhou L, et al. Identification of histone deacetylase 3 as a biomarker for tumor recurrence following liver transplantation in HBV-associated hepatocellular carcinoma. PLoS One. 2010;5:e14460.CrossRefGoogle Scholar
  82. 82.
    Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000;14:2393–409.PubMedCrossRefGoogle Scholar
  83. 83.
    Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology. 2008;47:2059–67.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Kaposi-Novak P, Lee JS, Gomez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest. 2006;116:1582–95.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Llovet JM, Pena CE, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2290–300.PubMedCrossRefGoogle Scholar
  86. 86.
    Schoenleber SJ, Kurtz DM, Talwalkar JA, et al. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer. 2009;100:1385–92.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Zhang W, Kim R, Quintini C, et al. Prognostic role of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma undergoing liver transplantation. Liver Transplant. 2015;21:101–11.CrossRefGoogle Scholar
  88. 88.
    Cheng AL, Kang YK, Chen Z, et al. 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. 2009;10:25–34.PubMedCrossRefGoogle Scholar
  89. 89.
    Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–71.PubMedCrossRefGoogle Scholar
  92. 92.
    Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011;47:2117–27.PubMedCrossRefGoogle Scholar
  93. 93.
    Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64:1090–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154–60.PubMedCrossRefGoogle Scholar
  95. 95.
    Barone C, Basso M, Biolato M, et al. A phase II study of sunitinib in advanced hepatocellular carcinoma. Dig Liver dis. 2013;45:692–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Faivre S, Raymond E, Boucher E, 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
  97. 97.
    Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067–75.PubMedCrossRefGoogle Scholar
  98. 98.
    Bruix J, Merle P, Granito A, et al. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma progressing on sorafenib: results of the international, randomized phase 3 Resorce trial. Esmo World Congress on Gastrointestinal Cancer. Abstract Lba-03. Presented June 30, 2016.Google Scholar
  99. 99.
    Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist. 2012;17:1063–72.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26:2992–8.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    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;24:1898–903.PubMedCrossRefGoogle Scholar
  102. 102.
    Hsu CH, Yang TS, Hsu C, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sun W, Sohal D, Haller DG, et al. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer. 2011;117:3187–92.PubMedCrossRefGoogle Scholar
  104. 104.
    Britten CD, Gomes AS, Wainberg ZA, et al. Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: a pilot study. BMC Cancer. 2012;12:16.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509–16.PubMedCrossRefGoogle Scholar
  106. 106.
    Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517–24.PubMedCrossRefGoogle Scholar
  107. 107.
    Toh HC, Chen PJ, Carr BI, et al. Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer. 2013;119:380–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Sandhu DS, Baichoo E, Roberts LR. Fibroblast growth factor signaling in liver carcinogenesis. Hepatology. 2014;59:1166–73.PubMedCrossRefGoogle Scholar
  110. 110.
    Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.PubMedCrossRefGoogle Scholar
  111. 111.
    French DM, Lin BC, Wang M, et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One. 2012;7:e36713.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Hagel M, Miduturu C, Sheets M, et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 2015;5:424–37.PubMedCrossRefGoogle Scholar
  113. 113.
    Schmidt B, Wei L, Deperalta DK, et al. Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition. Int J Cancer. 2016;138:1494–505.PubMedCrossRefGoogle Scholar
  114. 114.
    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;23:6657–63.PubMedCrossRefGoogle Scholar
  115. 115.
    Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;110:1059–67.PubMedCrossRefGoogle Scholar
  116. 116.
    Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559–66.PubMedCrossRefGoogle Scholar
  117. 117.
    Philip PA, Mahoney MR, Holen KD, et al. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012;118:2424–30.PubMedCrossRefGoogle Scholar
  118. 118.
    Xiang Q, Chen W, Ren M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res. 2014;20:2959–70.PubMedCrossRefGoogle Scholar
  119. 119.
    Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55–63.PubMedCrossRefGoogle Scholar
  120. 120.
    Giannelli G, Villa E, Lahn M. Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014;74:1890–4.PubMedCrossRefGoogle Scholar
  121. 121.
    Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.PubMedCrossRefGoogle Scholar
  122. 122.
    Dituri F, Mazzocca A, Fernando J, et al. Differential inhibition of the TGF-beta signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-beta receptor type II. PLoS One. 2013;8:e67109.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, Waldschmidt D, Mulcahy MF, Costentin C, Minguez B, Papappicco P, Gueorguieva I, Cleverly A, Desaiah D, Lahn MMF, Murray N, Benhadji KA, Raymond E, Giannelli G. Randomized dose comparison phase II study of the oral transforming growth factor-Beta (Tgf-S) receptor I kinase inhibitor Ly2157299 monohydrate (Ly) in patients with advanced hepatocellular carcinoma (Hcc). Asco gastrointestinal cancers symposium; 2014.Google Scholar
  124. 124.
    Lim HY, Heo J, Choi HJ, et al. A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin Cancer Res. 2014;20:5976–85.PubMedCrossRefGoogle Scholar
  125. 125.
    Rossi AG, Sawatzky DA, Walker A, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med. 2006;12:1056–64.PubMedCrossRefGoogle Scholar
  126. 126.
    Fornari F, Gramantieri L, Ferracin M, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27:5651–61.PubMedCrossRefGoogle Scholar
  127. 127.
    Cho SJ, Lee SS, Kim YJ, et al. Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Cancer Lett. 2010;287:196–206.PubMedCrossRefGoogle Scholar
  128. 128.
    Rivadeneira DB, Mayhew CN, Thangavel C, et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology. 2010;138:1920–30.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Haider C, Grubinger M, Reznickova E, et al. Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance. Mol Cancer Ther. 2013;12:1947–57.PubMedCrossRefGoogle Scholar
  130. 130.
    Semela D, Piguet AC, Kolev M, et al. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol. 2007;46:840–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Zhu AX, Abrams TA, Miksad R, et al. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer. 2011;117:5094–102.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Huynh H, Hao HX, Chan SL, et al. Loss of tuberous sclerosis complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mTORC1 inhibitor Everolimus. Mol Cancer Ther. 2015;14:1224–35.PubMedCrossRefGoogle Scholar
  133. 133.
    Khan O, Fotheringham S, Wood V, et al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc Natl Acad Sci U S A. 2010;107:6532–7.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Yeo W, Chung HC, Chan SL, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo phase II consortium and the cancer therapeutics research group. J Clin Oncol. 2012;30:3361–7.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Marquez-Rodas I, Cerezuela P, Soria A, et al. Immune checkpoint inhibitors: therapeutic advances in melanoma. Ann Transl Med. 2015;3:267.PubMedPubMedCentralGoogle Scholar
  136. 136.
    El-Khoueiry AB, Ignacio M, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (Hcc): CA209-040. J Clin Oncol. 2015;33(Suppl; Abstr Lba101).Google Scholar
  137. 137.
    Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200.PubMedCrossRefGoogle Scholar
  138. 138.
    Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16:1344–54.PubMedCrossRefGoogle Scholar
  139. 139.
    Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726–36.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Stephanie H. Greco
    • 1
  • Kristen Spencer
    • 1
  • Darren R. Carpizo
    • 1
    Email author
  1. 1.Rutgers Cancer Institute of New JerseyNew BrunswickUSA

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