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Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination

Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensit...

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Autores principales: Ham, Jungoh, Costa, Carlotta, Sano, Renata, Lochmann, Timothy L., Sennott, Erin M., Patel, Neha U., Dastur, Anahita, Gomez-Caraballo, Maria, Krytska, Kateryna, Hata, Aaron N., Floros, Konstantinos V., Hughes, Mark T., Jakubik, Charles T., Heisey, Daniel A.R., Ferrell, Justin T., Bristol, Molly L., March, Ryan J., Yates, Craig, Hicks, Mark A., Nakajima, Wataru, Gowda, Madhu, Windle, Brad E., Dozmorov, Mikhail G., Garnett, Mathew J., McDermott, Ultan, Harada, Hisashi, Taylor, Shirley M., Morgan, Iain M., Benes, Cyril H., Engelman, Jeffrey A., Mossé, Yael P., Faber, Anthony C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749542/
https://www.ncbi.nlm.nih.gov/pubmed/26859456
http://dx.doi.org/10.1016/j.ccell.2016.01.002
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author Ham, Jungoh
Costa, Carlotta
Sano, Renata
Lochmann, Timothy L.
Sennott, Erin M.
Patel, Neha U.
Dastur, Anahita
Gomez-Caraballo, Maria
Krytska, Kateryna
Hata, Aaron N.
Floros, Konstantinos V.
Hughes, Mark T.
Jakubik, Charles T.
Heisey, Daniel A.R.
Ferrell, Justin T.
Bristol, Molly L.
March, Ryan J.
Yates, Craig
Hicks, Mark A.
Nakajima, Wataru
Gowda, Madhu
Windle, Brad E.
Dozmorov, Mikhail G.
Garnett, Mathew J.
McDermott, Ultan
Harada, Hisashi
Taylor, Shirley M.
Morgan, Iain M.
Benes, Cyril H.
Engelman, Jeffrey A.
Mossé, Yael P.
Faber, Anthony C.
author_facet Ham, Jungoh
Costa, Carlotta
Sano, Renata
Lochmann, Timothy L.
Sennott, Erin M.
Patel, Neha U.
Dastur, Anahita
Gomez-Caraballo, Maria
Krytska, Kateryna
Hata, Aaron N.
Floros, Konstantinos V.
Hughes, Mark T.
Jakubik, Charles T.
Heisey, Daniel A.R.
Ferrell, Justin T.
Bristol, Molly L.
March, Ryan J.
Yates, Craig
Hicks, Mark A.
Nakajima, Wataru
Gowda, Madhu
Windle, Brad E.
Dozmorov, Mikhail G.
Garnett, Mathew J.
McDermott, Ultan
Harada, Hisashi
Taylor, Shirley M.
Morgan, Iain M.
Benes, Cyril H.
Engelman, Jeffrey A.
Mossé, Yael P.
Faber, Anthony C.
author_sort Ham, Jungoh
collection PubMed
description Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
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spelling pubmed-47495422016-02-29 Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination Ham, Jungoh Costa, Carlotta Sano, Renata Lochmann, Timothy L. Sennott, Erin M. Patel, Neha U. Dastur, Anahita Gomez-Caraballo, Maria Krytska, Kateryna Hata, Aaron N. Floros, Konstantinos V. Hughes, Mark T. Jakubik, Charles T. Heisey, Daniel A.R. Ferrell, Justin T. Bristol, Molly L. March, Ryan J. Yates, Craig Hicks, Mark A. Nakajima, Wataru Gowda, Madhu Windle, Brad E. Dozmorov, Mikhail G. Garnett, Mathew J. McDermott, Ultan Harada, Hisashi Taylor, Shirley M. Morgan, Iain M. Benes, Cyril H. Engelman, Jeffrey A. Mossé, Yael P. Faber, Anthony C. Cancer Cell Article Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression. Cell Press 2016-02-08 /pmc/articles/PMC4749542/ /pubmed/26859456 http://dx.doi.org/10.1016/j.ccell.2016.01.002 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ham, Jungoh
Costa, Carlotta
Sano, Renata
Lochmann, Timothy L.
Sennott, Erin M.
Patel, Neha U.
Dastur, Anahita
Gomez-Caraballo, Maria
Krytska, Kateryna
Hata, Aaron N.
Floros, Konstantinos V.
Hughes, Mark T.
Jakubik, Charles T.
Heisey, Daniel A.R.
Ferrell, Justin T.
Bristol, Molly L.
March, Ryan J.
Yates, Craig
Hicks, Mark A.
Nakajima, Wataru
Gowda, Madhu
Windle, Brad E.
Dozmorov, Mikhail G.
Garnett, Mathew J.
McDermott, Ultan
Harada, Hisashi
Taylor, Shirley M.
Morgan, Iain M.
Benes, Cyril H.
Engelman, Jeffrey A.
Mossé, Yael P.
Faber, Anthony C.
Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title_full Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title_fullStr Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title_full_unstemmed Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title_short Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
title_sort exploitation of the apoptosis-primed state of mycn-amplified neuroblastoma to develop a potent and specific targeted therapy combination
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749542/
https://www.ncbi.nlm.nih.gov/pubmed/26859456
http://dx.doi.org/10.1016/j.ccell.2016.01.002
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