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

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 YungAmar Gajjar, Clinton F. Stewart, R. Kiplin Guy, Richard J. Gilbertson

Research output: Contribution to journalArticle

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)384-399
Number of pages16
JournalCancer Cell
Volume20
Issue number3
DOIs
StatePublished - Sep 1 2011

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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    Atkinson, J. M., Shelat, A. A., Carcaboso, A. M., Kranenburg, T. A., Arnold, L. A., Boulos, N., Wright, K., Johnson, R. A., Poppleton, H., Mohankumar, K. M., Féau, C., Phoenix, T., Gibson, P., Zhu, L., Tong, Y., Eden, C., Ellison, D. W., Priebe, W., Koul, D., ... Gilbertson, R. J. (2011). An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell, 20(3), 384-399. https://doi.org/10.1016/j.ccr.2011.08.013