Presentation Abstract

Abstract Number: 4818
Presentation Title: The predictive value of a 5-gene signature as a patient pre-selection tool in medulloblastoma for Hedgehog pathway inhibitor therapy
Presentation Time: Tuesday, Apr 03, 2012, 3:05 PM - 3:20 PM
Location: McCormick Place West (Level 1), Room W192
Author Block: Dereck Amakye1, Douglas Robinson2, Kristine Rose1, Jae Cho3, Keith L. Ligon4, Thad Sharp1, Asifa Haider1, Raj Bandaru2, Yuichi Ando5, Birgit Geoerger6, Francois Doz7, David Ashley8, Darren Hargrave9, Michela Casanova10, Jordi Rodon11, Anne Thomas12, Alain Mita13, Tobey MacDonald14, Mark W. Kieran4. 1Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2Novartis Institutes for BioMedical Research, Cambridge, MA; 3Stanford School of Medicine, Palo Alto, CA; 4Dana-Farber Children’s Hospital Cancer Center, Boston, MA; 5Nagoya University Hospital, Nagoya, Japan; 6Institut Gustave Roussy, University Paris-Sud, Villejuif, France; 7Institut Curie and University Paris Descartes, Paris, France; 8Deakin University/Barwon Health, Melbourne, Australia; 9Great Ormond Street Hospital for Children, London, United Kingdom; 10Istituto Nazionale Tumori, Milano, Italy; 11Vall d’Hebron Institut d’Oncologia, Barcelona, Spain; 12University of Leicester, Leicester, United Kingdom; 13Cancer Therapy and Research Center, San Antonio, TX; 14Children’s Healthcare of Atlanta, Emory Children’s Center, Atlanta, GA
Abstract Body: Medulloblastoma (MB), an invasive primitive neuroectodermal tumor of the posterior fossa, is the most common brain tumor in children, comprising ~20% of childhood and <2% of adult brain tumors. Current standard of care treatment, surgery followed by craniospinal radiation and chemotherapy, can lead to significant long term toxicities, especially in very young patients. At the time of relapse, no standard salvage therapy exists. Therefore, targeted therapies are needed. Several studies have used gene expression profiling to identify distinct molecular subgroups of MB, including one characterized by activated Hedgehog (Hh) signaling. Using available gene expression data, a 5-gene Hh signature that can be assayed in formalin-fixed paraffin-embedded (FFPE) samples by standard RT-PCR was identified.
Two sets of matched fresh frozen and FFPE MB specimens were used; one for development of the 5-gene signature and one for its independent validation. Hh activation status was determined in fresh frozen samples by gene expression profiling using the GeneChip human genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA) and in FFPE samples by RT-PCR analysis.
The 5-gene Hh signature was selected from a larger panel of 73 genes that were associated with the Hh subgroup classification, as determined by standard Affymetrix gene expression profiling. Eighteen of these genes shown to be differentially expressed in FFPE were chosen for the RT-PCR gene card that formed the basis of the Elastic Net model building exercise. Based on the expression levels of the 5-gene signature, a predictive model was used to compute a propensity score (0-100%) representative of the Hh activation status of each tumor sample. The median propensity scores for the 17 non-Hh-activated tumors was 0.7% (range: 0.1-3.0%) compared to 87.9% (range: 69.1-97.6%) in the eight Hh-activated tumors. Hh activation status of 25 independent MB samples defined by the 5-gene signature and assayed by RT-PCR were in 100% agreement with the Hh activation status determined by gene expression profiling. In order to determine the predictive value of this assay as a tool to identify patients who might benefit from treatment with a Hh pathway inhibitor, MB samples from patients (n=13) enrolled in recent phase I trials of the Smoothened inhibitor LDE225 were analyzed and correlated with the respective tumor responses. Using the 5-gene signature, all patients (n=4) who responded to LDE225 treatment (PR or CR) were found to have Hh-pathway activated tumors, whereas all patients who did not respond (n=9) were found to have Hh non-activated tumors. These results suggest an association between Hh activation status determined by the 5-gene Hh signature and tumor response to LDE225 treatment. Data from an ongoing phase I/II trial in pediatric patients will enable determination of the predictive value of this patient pre-selection assay.