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

// Maria Wiese 1 , Neele Walther 1 , Christopher Diederichs 1 , Fabian Schill 1 , Sebastian Monecke 2 , Gabriela Salinas 3 , Dominik Sturm 4 , Stefan M. Pfister 4, 5 , Ralf Dressel 2 , Steven A. Johnsen 6 , Christof M. Kramm 1 1 Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Goettingen, Goettingen, Germany 2 Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, Goettingen, Germany 3 Transcriptome and Genome Analysis Laboratory (TAL), Department of Developmental Biochemistry, University Medical Center Goettingen, Goettingen, Germany 4 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany 6 Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany Correspondence to: Maria Wiese, email: maria.wiese@med.uni-goettingen.de Keywords: ICG-001, pediatric high-grade glioma (pedHGG), Wnt/β-catenin signaling, CREB binding protein (CBP), cell cycle Received: July 14, 2016      Accepted: February 20, 2017      Published: March 06, 2017 ABSTRACT 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.