title: IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.
abstract: OBJECTIVE
  IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway.
  
  
  METHODS
  An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC.
  
  
  RESULTS
  Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis.
  
  
  CONCLUSIONS
  Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.
authors.affiliation: HCC Translational Laboratory, BCLC Group, Liver Unit and Pathology Department, Hospital Clínic, CIBERehd, IDIBAPS, c/Villarroel 170, Catalonia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tovar
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
authors.forename: Manel
authors.initials: M
authors.lastname: Solé
authors.forename: Swan
authors.initials: S
authors.lastname: Thung
authors.forename: Susana
authors.initials: S
authors.lastname: Moyano
authors.forename: Sara
authors.initials: S
authors.lastname: Toffanin
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mínguez
authors.forename: Laia
authors.initials: L
authors.lastname: Cabellos
authors.forename: Judit
authors.initials: J
authors.lastname: Peix
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002455:Cell Division / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C515497:IGFBP3 protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; C544266:MIRN100 microRNA, human; D035683:MicroRNAs; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1