title: Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model.
abstract: OBJECTIVE
  Hepatocellular cancer (HCC) remains a disease of poor prognosis, highlighting the relevance of elucidating key molecular aberrations that may be targeted for novel therapies. Wnt signalling activation, chiefly due to mutations in CTNNB1, have been identified in a major subset of HCC patients. While several in vitro proof of concept studies show the relevance of suppressing Wnt/β-catenin signalling in HCC cells or tumour xenograft models, no study has addressed the impact of β-catenin inhibition in a relevant murine HCC model driven by Ctnnb1 mutations.
  
  
  METHODS
  We studied the in vivo impact of β-catenin suppression by locked nucleic acid (LNA) antisense treatment, after establishing Ctnnb1 mutation-driven HCC by diethylnitrosamine and phenobarbital (DEN/PB) administration.
  
  
  RESULTS
  The efficacy of LNA directed against β-catenin vs. scrambled on Wnt signalling was demonstrated in vitro in HCC cells and in vivo in normal mice. The DEN/PB model leads to HCC with Ctnnb1 mutations. A complete therapeutic response in the form of abrogation of HCC was observed after ten treatments of tumour-bearing mice with β-catenin LNA every 48h as compared to the scrambled control. A decrease in β-catenin activity, cell proliferation and increased cell death was evident after β-catenin suppression. No effect of β-catenin suppression was evident in non-Ctnnb1 mutated HCC, observed after DEN-only administration.
  
  
  CONCLUSIONS
  Thus, we provide the in vivo proof of concept that β-catenin suppression in HCC will be of significant therapeutic benefit, provided the tumours display Wnt activation via mechanisms like CTNNB1 mutations.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Delgado
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Okabe
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Preziosi
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jacquelyn Olivia
authors.initials: JO
authors.lastname: Russell
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Tamara Feliciano
authors.initials: TF
authors.lastname: Alvarado
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oertel
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Kari Nichole
authors.initials: KN
authors.lastname: Nejak-Bowen
authors.affiliation: Enzon Pharmaceuticals, New Jersey, USA.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: smonga@pitt.edu.
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000477:Alkylating Agents / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004052:Diethylnitrosamine / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D009841:Oligonucleotides / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; C495267:CTNNB1 protein, mouse; D004273:DNA, Neoplasm; D018691:Excitatory Amino Acid Antagonists; D009841:Oligonucleotides; D051176:beta Catenin; C477371:locked nucleic acid; D004052:Diethylnitrosamine; D010634:Phenobarbital
keywords: Hepatocellular cancer; Molecular therapy; Mutations; Oncogene; Targeted therapy; Wnt signalling