An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma.

Abstract

Using a mouse model of ependymoma-a chemoresistant brain tumor-we combined multicell high-throughput screening (HTS), kinome-wide binding assays, and in vivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both in vitro and in vivo, e.g., 5-fluorouracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation.

• Authors: Jennifer M Atkinson, Anang A Shelat, Angel Montero Carcaboso, Tanya A Kranenburg, Leggy A Arnold, Nidal Boulos, Karen Wright, Robert A Johnson, Helen Poppleton, Kumarasamypet M Mohankumar, Clementine Féau, Timothy Phoenix, Paul Gibson, Liqin Zhu, Yiai Tong, Chris Eden, David W Ellison, Waldemar Priebe, Dimpy Koul, W K Alfred Yung, Amar Gajjar, Clinton F Stewart, R Kiplin Guy, Richard J Gilbertson
• Journal: Cancer cell (Cancer Cell) Vol. 20 Issue 3 Pg. 384-99 (Sep 13 2011) ISSN: 1878-3686 [Electronic] United States
• PMID: 21907928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Boronic Acids
• Insulin
• Pyrazines
• Bortezomib
• Fluorouracil

Topics

• Animals
• Boronic Acids (pharmacology)
• Bortezomib
• Brain (pathology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Centrosome (metabolism)
• Drug Screening Assays, Antitumor
• Ependymoma (drug therapy, metabolism, pathology)
• Fluorouracil (pharmacology)
• High-Throughput Screening Assays (methods)
• Insulin (metabolism)
• Mice
• Mice, Nude
• Neural Stem Cells (drug effects)
• Pyrazines (pharmacology)
• Signal Transduction
• Tumor Cells, Cultured