title: Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.
abstract: BACKGROUND
  Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches.
  
  
  METHODS
  We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models.
  
  
  RESULTS
  We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways.
  
  
  CONCLUSIONS
  These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.
authors.affiliation: University of Turin Medical School, Department of Oncology, IRCCS-Candiolo, Strada provinciale 142, Km 3,95, Candiolo, 10060 Turin, Italy. caterina.peraldoneia@ircc.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Peraldo-Neia
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cavalloni
authors.forename: Marco
authors.initials: M
authors.lastname: Soster
authors.forename: Loretta
authors.initials: L
authors.lastname: Gammaitoni
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Capussotti
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Francesco
authors.initials: F
authors.lastname: Leone
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001661:Biliary Tract Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; C468783:H2AX protein, human; D053823:Hedgehog Proteins; D006657:Histones; D015850:Interleukin-6; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000077606:Trabectedin