A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma

Shou, Y, Robinson, DM, Amakye, DD, Rose, KL, Cho, YJ, Ligon, KL, Sharp, T, Haider, AS, Bandaru, R, Ando, Y, Geoerger, B, Doz, F, Ashley, DM, Hargrave, DR, Casanova, M, Tawbi, HA, Rodon, J, Thomas, AL, Mita, AC, MacDonald, TJ and Kieran, MW 2015, A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma, Clinical cancer research, vol. 21, no. 3, pp. 585-593, doi: 10.1158/1078-0432.CCR-13-1711.

Attached Files
Name Description MIMEType Size Downloads

Title A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma
Author(s) Shou, Y
Robinson, DM
Amakye, DD
Rose, KL
Cho, YJ
Ligon, KL
Sharp, T
Haider, AS
Bandaru, R
Ando, Y
Geoerger, B
Doz, F
Ashley, DM
Hargrave, DR
Casanova, M
Tawbi, HA
Rodon, J
Thomas, AL
Mita, AC
MacDonald, TJ
Kieran, MW
Journal name Clinical cancer research
Volume number 21
Issue number 3
Start page 585
End page 593
Total pages 9
Publisher American Association for Cancer Research
Place of publication Philadelphia, PA
Publication date 2015-02-01
ISSN 1078-0432
Keyword(s) gene expression profiling
molecular modeling
Phase I-III trials_Brain/central nervous system cancers
novel antitumor agents
five-gene Hh signature assay
sonidegib (LDE225)
Summary Purpose: 
Distinct molecular subgroups of medulloblastoma (MB), including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated MB.

Experimental Design:
Genes characteristic of the Hh MB subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. Based on signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.

Five differentially expressed genes in MB (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 MB samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in MB samples from 50 patients treated with sonidegib, all six patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded.

This five-gene Hh signature can robustly identify Hh-activated MB and may be used to preselect patients who might benefit from sonidegib treatment.
Language eng
DOI 10.1158/1078-0432.CCR-13-1711
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, American Association for Cancer Research
Persistent URL http://hdl.handle.net/10536/DRO/DU:30068239

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Connect to link resolver
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 27 times in TR Web of Science
Scopus Citation Count Cited 26 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 240 Abstract Views, 4 File Downloads  -  Detailed Statistics
Created: Tue, 16 Dec 2014, 08:58:14 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.