ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 50 P273 | DOI: 10.1530/endoabs.50.P273

Cyclooxygenase-2 is a potential target for the treatment of Adamantinomatous craniopharyngioma

Valeria Scagliotti1, Lorena Perez Gutierrez1, Angelica Gualtieri1, Fernando Jimenez1, Nicholas Kirkby1,2, Jane Mitchell2, Timothy Warner1, Evelien Gevers1, Mehul Dattani3 & Carles Gaston-Massuet1

1William Harvey Research Institute, London, UK; 2National Heart & Lung Insitute, London, UK; 3Institute of Child Health, London, UK.

Adamantinomatous craniopharyngiomas (ACPs) are among the most common intracranial tumours in children and they originate from undifferentiated pituitary progenitors. Mutations in the gene encoding for β-catenin (CTNNB1), which lead to the constitutive activation of the Wnt/β-catenin signalling pathway, have been associated with ACP. These tumours can invade adjacent structures, such as the hypothalamus, which makes complete resection difficult, leading to a high rate of recurrences and co-morbidities associated to the treatment. No pharmacological treatment currently exists for this condition. To identify new possible targets, we used microarray analysis to compare gene expression of pituitaries isolated from WT mice and from our mouse model of ACP. Our microarray data showed up-regulation of the cyclooxygenase-2 (COX-2)-encoding gene (Ptgs-2) in the ACP samples. COX-2 has been associated with poor prognosis in cancer and COX-2-inhibitors have been indicated as potential anti-cancer agents. To assess whether valdecoxib, a COX-2-selective inhibitor, also affects the activity of the Wnt/β-catenin signalling pathway, we used the Wnt-signalling reporter assay TOPFlash in a HEK-293T cell line treated with valdecoxib. Importantly, valdecoxib effectively repressed β-catenin transcriptional activity in a dose-dependent manner (up to 99% reduction compared to the control, n=3 in triplicate). In addition, our immunofluorescence analysis revealed for the first time COX-2 expression in the pituitary progenitors/stem cells (PPSCs) isolated from WT and ACP-mice. Notably, one week-treatment with valdecoxib of PPSCs isolated from murine ACP samples significantly impaired the proliferation capacity of the progenitors in vitro. In conclusion, we show for the first time that valdecoxib, a highly-selective COX-2-inhibitor, has also a highly inhibitory effect on the Wnt-canonical pathway signalling, hence reducing the proliferation and clonogenic potential of ACP-progenitor cells in vitro. Therefore, our data suggest that valdecoxib represents a promising candidate for novel and efficacious treatments for ACP.