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Molecular targets for HCC and future treatments

  • Manon Allaire
    Affiliations
    Service d’Hépato-Gastroentérologie, CHU Côte de Nacre, Caen, France
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  • Jean-Charles Nault
    Correspondence
    Corresponding author. Address: APHP, Hôpitaux universitaires Paris – Seine Saint Denis, Site Jean Verdier, Pôle d’Activité Cancérologique spécialisée, Service d’Hépatologie, F-93143 Bondy, France. Tel.: +33 1 53 72 51 94; fax: +33 1 53 72 51 92.
    Affiliations
    Service d’hépatologie, Hôpital Jean Verdier, Hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance-publique Hôpitaux de Paris, Bondy, France

    Unité mixte de Recherche 1162, Génomique fonctionnelle des Tumeurs solides, Institut National de la Santé et de la Recherche médicale, Paris, France

    Unité de Formation et de Recherche Santé Médecine et Biologie humaine, Université Paris 13, Communauté d’Universités et Etablissements Sorbonne Paris Cité, Paris, France
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Published:November 09, 2016DOI:https://doi.org/10.1016/j.jhep.2016.07.034
      Subversion of the microenvironment and neo-angiogenesis promote tumor progression, vascular invasion and metastasis [
      • Makarova-Rusher O.V.
      • Medina-Echeverz J.
      • Duffy A.G.
      • Greten T.F.
      The yin and yang of evasion and immune activation in HCC.
      ]. Two tyrosine kinase inhibitors with anti-angiogenic properties, sorafenib and regorafenib, have been shown to improve survival of patients with advanced hepatocellular carcinoma (HCC) in first and second lines of treatment, respectively [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,

      Bayer’s regorafenib significantly improves overall survival in patients with unresectable liver cancer. http://www.news.bayer.com/baynews/baynews.nsf/id/Bayers-Regorafenib-Significantly-Improves-Overall-Survival-Patients-Unresectable-Liver-Cancer.

      ]. Moreover, the anti-tumor response by the immune system is repressed through several mechanisms that involve not only tumor cells, but also other cells of the microenvironment. The PD1/PDL1 (programmed cell death 1/programmed cell death ligand 1) and CTLA4 (cytotoxic T-lymphocyte-associated protein 4) systems inhibit T cells and are currently the main targets of immunotherapy in solid cancers [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      ]. Inhibition of immune checkpoints by specific antibodies foster an anti-tumor response by the immune system. Clinical trials testing antibodies against PD1 (nivolumab) or PDL1 (darvalumab) and against CTLA4 (tremelimumab, ipilimumab) are on-going in advanced HCC.
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      References

      Author names in bold designate shared co-first authorship

        • Makarova-Rusher O.V.
        • Medina-Echeverz J.
        • Duffy A.G.
        • Greten T.F.
        The yin and yang of evasion and immune activation in HCC.
        J Hepatol. 2015; 62: 1420-1429
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
      1. Bayer’s regorafenib significantly improves overall survival in patients with unresectable liver cancer. http://www.news.bayer.com/baynews/baynews.nsf/id/Bayers-Regorafenib-Significantly-Improves-Overall-Survival-Patients-Unresectable-Liver-Cancer.

        • Borghaei H.
        • Paz-Ares L.
        • Horn L.
        • Spigel D.R.
        • Steins M.
        • Ready N.E.
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639
        • Schulze K.
        • Imbeaud S.
        • Letouze E.
        • Alexandrov L.B.
        • Calderaro J.
        • Rebouissou S.
        • et al.
        Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
        Nat Genet. 2015; 47: 505-511
        • Totoki Y.
        • Tatsuno K.
        • Covington K.R.
        • Ueda H.
        • Creighton C.J.
        • Kato M.
        • et al.
        Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.
        Nat Genet. 2014; 46: 1267-1273
        • Zucman-Rossi J.
        • Villanueva A.
        • Nault J.C.
        • Llovet J.M.
        Genetic landscape and biomarkers of hepatocellular carcinoma.
        Gastroenterology. 2015; 149: 1226-1239e1224
        • Guichard C.
        • Amaddeo G.
        • Imbeaud S.
        • Ladeiro Y.
        • Pelletier L.
        • Maad I.B.
        • et al.
        Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
        Nat Genet. 2012; 44: 694-698
        • Nault J.C.
        • Mallet M.
        • Pilati C.
        • Calderaro J.
        • Bioulac-Sage P.
        • Laurent C.
        • et al.
        High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
        Nat Commun. 2013; 4: 2218
        • Santoro A.
        • Rimassa L.
        • Borbath I.
        • Daniele B.
        • Salvagni S.
        • Van Laethem J.L.
        • et al.
        Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study.
        Lancet Oncol. 2013; 14: 55-63