The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner

Oncotarget. 2017 Apr 18;8(16):27300-27313. doi: 10.18632/oncotarget.15934.


Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.

Keywords: CREB binding protein (CBP); ICG-001; Wnt/β-catenin signaling; cell cycle; pediatric high-grade glioma (pedHGG).

MeSH terms

  • Adolescent
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • CREB-Binding Protein / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Self Renewal / drug effects
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Chick Embryo
  • Child
  • Child, Preschool
  • Databases, Genetic
  • Disease Models, Animal
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / mortality
  • Glioma / pathology
  • Humans
  • Kaplan-Meier Estimate
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Prognosis
  • Pyrimidinones / pharmacology*
  • Wnt Signaling Pathway / drug effects*
  • Young Adult
  • beta Catenin / antagonists & inhibitors*


  • Bridged Bicyclo Compounds, Heterocyclic
  • ICG 001
  • Pyrimidinones
  • beta Catenin
  • CREB-Binding Protein
  • CREBBP protein, human