OR53-2 Genetic and in vitro inhibition of the Wnt/β-catenin pathway results in amelioration of adamantinomatous craniopharyngioma

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR53-Transcriptional Regulators & Epigenetic Control
Basic/Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:30 AM
Room 133 (Moscone Center)
Carles Gaston-Massuet*, Paul R. Le Tissier, Mehul Tulsidas Dattani and Juan Pedro Martinez-Barbera
UCL, London, United Kingdom
The Wnt/β-catenin signalling pathway is required during embryonic development for normal cell proliferation, differentiation and organ homeostasis. Previously, we have shown that the Wnt/β-catenin pathway needs to be antagonised during early anterior pituitary (AP) development to maintain the appropriate numbers of progenitor cells. Over-activation of this pathway, by conditional expression of a degradation-resistant form of β-catenin (Ctnnb1flox(ex3)) in the undifferentiated precursors of the pituitary gland (Hesx1Cre/+;Ctnnb1flox(ex3)/+) results in hypopituitarism, severe hyperplasia and adamantinomatous craniopharyngioma (ACP)-like tumors.  This finding demonstrated for the first time a causal effect of mutations in β-catenin in ACP, and provided a novel animal model to further study ACP pathogenesis. ACPs are epithelial tumours that arise in the sellar and suprasellar region and account for 5-10% of intracranial tumors in children, causing severe endocrine and neurological disturbances. Current therapy includes radical surgery which is associated with considerable morbidity and recurrence of the tumour. More recently, a combination of limited surgery combined with radiotherapy has been advocated as generating better outcomes. This too is associated with significant morbidity, and there is therefore a need for alternative therapeutic treatments. In order to identify novel therapies using Wnt/β-catenin inhibition in vivo, we generated a mouse that antagonises Wnt by expressing Hesx1 from the Rosa26 locus (Hesx1Cre/+;Ctnnb1flox(ex3)/+; R26Hesx1/+).  Median survival of these triple compound mice increased to 29 weeks compared to 12 weeks for the double compound mutants (Hesx1Cre/+;Ctnnb1flox(ex3)/+), indicating that in vivo inhibition of Wnt results in amelioration of  ACP  tumors. Over-expression of Hesx1 in these tumors led to restoration of wild-type levels of Lef1 and Axin2 (downstream targets of β-catenin). Moreover, Hesx1 overexpression inhibited proliferation and decreased clonogenic potential of pituitary progenitors/stem cells. Using an in vitro murine ACP-cell culture assay to identify Wnt/β-catenin inhibitory compounds with potential therapeutic effects on ACPs,  we showed that the two non-steroidal anti-inflammatory drugs indomethacin and sulindac sulfone have a strong inhibitory effect on cell colony assay growth, suggesting an ACP-inhibiting effect of these compounds in vitro. To assess their therapeutic potential in vivo, we treated the murine ACP model (Hesx1Cre/+;Ctnnb1flox(ex3)/+) with indomethacin; this resulted in an increased life–span, indicating an ameliorating effect of indomethacin treatment on ACP. Our data therefore raise the exciting prospect of the use of indomethacin and related compounds in patients with ACP, thereby potentially reducing morbidity and even mortality.

Nothing to Disclose: CG, PRL, MTD, JPM

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