Unknown

Dataset Information

0

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.

SUBMITTER: Faria CC 

PROVIDER: S-EPMC4673298 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 piperlongu  ...[more]

Similar Datasets

| S-EPMC2770235 | biostudies-literature
| S-EPMC6171097 | biostudies-literature
| S-EPMC11012547 | biostudies-literature
| S-EPMC4763784 | biostudies-literature
| S-EPMC64992 | biostudies-literature
| S-EPMC9747717 | biostudies-literature
| S-EPMC7164431 | biostudies-literature
| S-EPMC3067866 | biostudies-literature
| S-EPMC4598220 | biostudies-literature
| S-EPMC9465370 | biostudies-literature