SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma.

Abstract:

:Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow-up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through MRI-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Carreno G,Boult JKR,Apps J,Gonzalez-Meljem JM,Haston S,Guiho R,Stache C,Danielson LS,Koers A,Smith LM,Virasami A,Panousopoulos L,Buchfelder M,Jacques TS,Chesler L,Robinson SP,Martinez-Barbera JP

doi

10.1530/ERC-18-0538

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

355-366

issue

3

eissn

1351-0088

issn

1479-6821

pii

ERC-18-0538.R1

journal_volume

26

pub_type

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