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 Yung; Amar Gajjar; Clinton F. Stewart; R. Kiplin Guy; Richard J. Gilbertson

doi:10.1016/j.ccr.2011.08.013

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 journal › Article › peer-review

94 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 language	English
Pages (from-to)	384-399
Number of pages	16
Journal	Cancer Cell
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.08.013
State	Published - Sep 2011

Bibliographical note

Funding Information:
R.J.G. holds the Howard C. Schott Research Chair from the Malia's Cord Foundation. R.K.G. holds the Robert J. Ullrich Chair in Chemical Biology and Therapeutics. This work was supported by grants from the National Institutes of Health (R.J.G., R01CA129541, P01CA96832 and P30CA021765), and the Collaborative Ependymoma Research Network (R.J.G., R.K.G., C.F.S., W.K.A.Y., W.P.) and by the American Lebanese Syrian Associated Charities. We are grateful to the staff of the Hartwell Center for Bioinformatics and Biotechnology, the AIC and the ARC at St Jude Children's Research Hospital for technical assistance.

Funding

R.J.G. holds the Howard C. Schott Research Chair from the Malia's Cord Foundation. R.K.G. holds the Robert J. Ullrich Chair in Chemical Biology and Therapeutics. This work was supported by grants from the National Institutes of Health (R.J.G., R01CA129541, P01CA96832 and P30CA021765), and the Collaborative Ependymoma Research Network (R.J.G., R.K.G., C.F.S., W.K.A.Y., W.P.) and by the American Lebanese Syrian Associated Charities. We are grateful to the staff of the Hartwell Center for Bioinformatics and Biotechnology, the AIC and the ARC at St Jude Children's Research Hospital for technical assistance.

Funders	Funder number
Collaborative Ependymoma Research Network
National Institutes of Health (NIH)	P30CA021765, P01CA96832
National Childhood Cancer Registry – National Cancer Institute	R01CA129541
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2011.08.013

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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

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title = "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.",

author = "Atkinson, {Jennifer M.} and Shelat, {Anang A.} and Carcaboso, {Angel Montero} and Kranenburg, {Tanya A.} and Arnold, {Leggy A.} and Nidal Boulos and Karen Wright and Johnson, {Robert A.} and Helen Poppleton and Mohankumar, {Kumarasamypet M.} and Clementine F{\'e}au and Timothy Phoenix and Paul Gibson and Liqin Zhu and Yiai Tong and Chris Eden and Ellison, {David W.} and Waldemar Priebe and Dimpy Koul and Yung, {W. K.Alfred} and Amar Gajjar and Stewart, {Clinton F.} and Guy, {R. Kiplin} and Gilbertson, {Richard J.}",

note = "Funding Information: R.J.G. holds the Howard C. Schott Research Chair from the Malia's Cord Foundation. R.K.G. holds the Robert J. Ullrich Chair in Chemical Biology and Therapeutics. This work was supported by grants from the National Institutes of Health (R.J.G., R01CA129541, P01CA96832 and P30CA021765), and the Collaborative Ependymoma Research Network (R.J.G., R.K.G., C.F.S., W.K.A.Y., W.P.) and by the American Lebanese Syrian Associated Charities. We are grateful to the staff of the Hartwell Center for Bioinformatics and Biotechnology, the AIC and the ARC at St Jude Children's Research Hospital for technical assistance. ",

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Atkinson, JM, Shelat, AA, Carcaboso, AM, Kranenburg, TA, Arnold, LA, Boulos, N, Wright, K, Johnson, RA, Poppleton, H, Mohankumar, KM, Féau, C, Phoenix, T, Gibson, P, Zhu, L, Tong, Y, Eden, C, Ellison, DW, Priebe, W, Koul, D, Yung, WKA, Gajjar, A, Stewart, CF, Guy, RK & Gilbertson, RJ 2011, 'An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma', Cancer Cell, vol. 20, no. 3, pp. 384-399. https://doi.org/10.1016/j.ccr.2011.08.013

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T1 - An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma

AU - Atkinson, Jennifer M.

AU - Shelat, Anang A.

AU - Carcaboso, Angel Montero

AU - Kranenburg, Tanya A.

AU - Arnold, Leggy A.

AU - Boulos, Nidal

AU - Wright, Karen

AU - Johnson, Robert A.

AU - Poppleton, Helen

AU - Mohankumar, Kumarasamypet M.

AU - Féau, Clementine

AU - Phoenix, Timothy

AU - Gibson, Paul

AU - Zhu, Liqin

AU - Tong, Yiai

AU - Eden, Chris

AU - Ellison, David W.

AU - Priebe, Waldemar

AU - Koul, Dimpy

AU - Yung, W. K.Alfred

AU - Gajjar, Amar

AU - Stewart, Clinton F.

AU - Guy, R. Kiplin

AU - Gilbertson, Richard J.

N1 - Funding Information: R.J.G. holds the Howard C. Schott Research Chair from the Malia's Cord Foundation. R.K.G. holds the Robert J. Ullrich Chair in Chemical Biology and Therapeutics. This work was supported by grants from the National Institutes of Health (R.J.G., R01CA129541, P01CA96832 and P30CA021765), and the Collaborative Ependymoma Research Network (R.J.G., R.K.G., C.F.S., W.K.A.Y., W.P.) and by the American Lebanese Syrian Associated Charities. We are grateful to the staff of the Hartwell Center for Bioinformatics and Biotechnology, the AIC and the ARC at St Jude Children's Research Hospital for technical assistance.

PY - 2011/9

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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