PT  - JOURNAL ARTICLE
AU  - Visnyei, Koppany
AU  - Onodera, Hideyuki
AU  - Damoiseaux, Robert
AU  - Saigusa, Kuniyasu
AU  - Petrosyan, Syuzanna
AU  - De Vries, David
AU  - Ferrari, Denise
AU  - Saxe, Jonathan
AU  - Panosyan, Eduard H.
AU  - Masterman-Smith, Michael
AU  - Mottahedeh, Jack
AU  - Bradley, Kenneth A.
AU  - Huang, Jing
AU  - Sabatti, Chiara
AU  - Nakano, Ichiro
AU  - Kornblum, Harley I.
TI  - A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells
AID  - 10.1158/1535-7163.MCT-11-0268
DP  - 2011 Oct 01
TA  - Molecular Cancer Therapeutics
PG  - 1818--1828
VI  - 10
IP  - 10
4099  - http://mct.aacrjournals.org/content/10/10/1818.short
4100  - http://mct.aacrjournals.org/content/10/10/1818.full
SO  - Mol Cancer Ther2011 Oct 01; 10
AB  - Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, n-arachidonoyl dopamine, n-oleoyldopamine (OLDA), and n-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types. Mol Cancer Ther; 10(10); 1818–28. ©2011 AACR.