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DOI: 10.1055/s-0036-1593548
The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner
Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with poor prognosis due to a lack of efficient therapeutic strategies. To identify therapeutic targets, intensive research in adult high-grade gliomas identified dysregulated and tumor-driving signal-transduction pathways. The β-catenin/Wnt-signaling pathway holds promising potential as treatment option in adults to abrogate tumor cell invasion and acquisition of “cancer stem cell” characteristics. However, pedHGG frequently differ from their adult counterparts with respect to tumor genetics and biology and observations from adult neurooncology cannot automatically be translated into pediatric setting. We therefore aimed to investigate the effects of β-catenin/Wnt-signaling pathway inhibition by the novel β-catenin/CBP-antagonist ICG-001 in two different pedHGG cell line models. In contrast to adult HGG that are characterized by strong β-catenin/Wnt signaling activity, the pedHGG cell lines KNS42 and UW479 displayed only barely detectable canonical Wnt-signaling activity. Thus, inhibition of cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, by comparatively low doses of ICG-001, probably occur independent of β-catenin/Wnt-signaling. Furthermore, mRNA sequencing analyses did not confirm a significant impact of ICG-001 on β-catenin target gene transcription, but revealed strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. ICG-001 induced strong upregulation of the cell cycle regulator JDP2 which we also found to confer a better prognosis for pedHGG patients when it is highly expressed. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients independent of canonical Wnt-signaling activity.