Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma
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Claudia C. Faria1,2,3,4, Sameer Agnihotri2, Stephen C. Mack5, Brian J. Golbourn2, Roberto J. Diaz1,2, Samantha Olsen2, Melissa Bryant2, Matthew Bebenek2, Xin Wang5, Kelsey C. Bertrand2, Michelle Kushida5, Renee Head5, Ian Clark5, Peter Dirks1,5, Christian A. Smith2, Michael D. Taylor1,5 and James T. Rutka1,2
1 Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada
2 Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
3 Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal
4 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
5 Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
James T. Rutka, email:
Keywords: group 3 medulloblastoma, alsterpaullone, piperlongumine, connectivity map
Received: March 18, 2015 Accepted: May 13, 2015 Published: May 28, 2015
Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.
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