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Endocr Relat Cancer. 2019 Jan 1. pii: ERC-18-0538.R1. doi: 10.1530/ERC-18-0538. [Epub ahead of print]

SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma.

Author information

1
G Carreno, Institute of Child Health, Developmental Biology and Cancer Programme, UCL Institute of Child Health, UCL, London, United Kingdom of Great Britain and Northern Ireland.
2
J Boult, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
3
J Apps, Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, United Kingdom of Great Britain and Northern Ireland.
4
J Gonzalez-Meljem, Basic Research Department, Instituto Nacional de Geriatria, Ciudad de Mexico, Mexico.
5
S Haston, Institute of Child Health, Developmental Biology and Cancer Programme, UCL Institute of Child Health, UCL, London, WC1N 1EH, United Kingdom of Great Britain and Northern Ireland.
6
R Guiho, Institute of Child Health, Developmental Biology and Cancer Programme, UCL Institute of Child Health, UCL, London, United Kingdom of Great Britain and Northern Ireland.
7
C Stache, Institute of Child Health, Developmental Biology and Cancer Programme, UCL Institute of Child Health, UCL, London, United Kingdom of Great Britain and Northern Ireland.
8
L Danielson, Division of Clinical Studies and Cancer Therapeutics Division, The Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
9
A Koers, Division of Clinical Studies and Cancer Therapeutics Division, The Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
10
L Smith, Division of Clinical Studies and Cancer Therapeutics Division, The Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
11
A Virasami, Department of Histopathology, Great Ormond Street Hospital for Children, London, United Kingdom of Great Britain and Northern Ireland.
12
L Panousopoulos, Institute of Child Health, Developmental Biology and Cancer Programme, UCL Institute of Child Health, UCL, London, United Kingdom of Great Britain and Northern Ireland.
13
M Buchfelder, Neurosurgery, University of Erlangen-Nuremberg, Erlangen, Germany.
14
T Jacques, Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, United Kingdom of Great Britain and Northern Ireland.
15
L Chesler, Paediatric Solid Tumour Biology and Therapeutics, The Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
16
S Robinson, Radiotherapy and Imaging, Institute of Cancer Research, London, United Kingdom of Great Britain and Northern Ireland.
17
J Martinez-Barbera, Institute of Child Health, Developmental Biology and Cancer Programme Birth Defects Research Centre, University College London, 30 Guilford Street , London, United Kingdom of Great Britain and Northern Ireland.

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 magnetic resonance imaging (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.

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