Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.

Abstract

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.

• Authors: Claudia C Faria, Sameer Agnihotri, Stephen C Mack, Brian J Golbourn, Roberto J Diaz, Samantha Olsen, Melissa Bryant, Matthew Bebenek, Xin Wang, Kelsey C Bertrand, Michelle Kushida, Renee Head, Ian Clark, Peter Dirks, Christian A Smith, Michael D Taylor, James T Rutka
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 25 Pg. 21718-29 (Aug 28 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26061748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Antineoplastic Agents
• Benzazepines
• Benzopyrans
• Dioxolanes
• Indoles
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• alsterpaullone
• RNA
• rottlerin
• Cyclin-Dependent Kinases
• piperlonguminine
• Flunarizine

Topics

• Acetophenones (chemistry)
• Animals
• Antineoplastic Agents (chemistry)
• Benzazepines (chemistry)
• Benzopyrans (chemistry)
• Brain Neoplasms (drug therapy)
• Cell Line
• Cell Proliferation
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Dioxolanes (chemistry)
• Drug Screening Assays, Antitumor
• Flunarizine (chemistry)
• Gene Expression Profiling
• Genomics
• Humans
• Indoles (chemistry)
• Medulloblastoma (drug therapy)
• Mice
• Neoplasm Metastasis
• Neoplasm Transplantation
• Prognosis
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA (metabolism)