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Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells

Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modul...

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Autores principales: Grinshtein, Natalie, Rioseco, Constanza C., Marcellus, Richard, Uehling, David, Aman, Ahmed, Lun, Xueqing, Muto, Osamu, Podmore, Lauren, Lever, Jake, Shen, Yaoqing, Blough, Michael D., Cairncross, Greg J., Robbins, Stephen M., Jones, Steven J., Marra, Marco A., Al-Awar, Rima, Senger, Donna L., Kaplan, David R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312317/
https://www.ncbi.nlm.nih.gov/pubmed/27449082
http://dx.doi.org/10.18632/oncotarget.10661
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author Grinshtein, Natalie
Rioseco, Constanza C.
Marcellus, Richard
Uehling, David
Aman, Ahmed
Lun, Xueqing
Muto, Osamu
Podmore, Lauren
Lever, Jake
Shen, Yaoqing
Blough, Michael D.
Cairncross, Greg J.
Robbins, Stephen M.
Jones, Steven J.
Marra, Marco A.
Al-Awar, Rima
Senger, Donna L.
Kaplan, David R.
author_facet Grinshtein, Natalie
Rioseco, Constanza C.
Marcellus, Richard
Uehling, David
Aman, Ahmed
Lun, Xueqing
Muto, Osamu
Podmore, Lauren
Lever, Jake
Shen, Yaoqing
Blough, Michael D.
Cairncross, Greg J.
Robbins, Stephen M.
Jones, Steven J.
Marra, Marco A.
Al-Awar, Rima
Senger, Donna L.
Kaplan, David R.
author_sort Grinshtein, Natalie
collection PubMed
description Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies.
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spelling pubmed-53123172017-03-06 Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells Grinshtein, Natalie Rioseco, Constanza C. Marcellus, Richard Uehling, David Aman, Ahmed Lun, Xueqing Muto, Osamu Podmore, Lauren Lever, Jake Shen, Yaoqing Blough, Michael D. Cairncross, Greg J. Robbins, Stephen M. Jones, Steven J. Marra, Marco A. Al-Awar, Rima Senger, Donna L. Kaplan, David R. Oncotarget Research Paper Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies. Impact Journals LLC 2016-07-18 /pmc/articles/PMC5312317/ /pubmed/27449082 http://dx.doi.org/10.18632/oncotarget.10661 Text en Copyright: © 2016 Grinshtein et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Grinshtein, Natalie
Rioseco, Constanza C.
Marcellus, Richard
Uehling, David
Aman, Ahmed
Lun, Xueqing
Muto, Osamu
Podmore, Lauren
Lever, Jake
Shen, Yaoqing
Blough, Michael D.
Cairncross, Greg J.
Robbins, Stephen M.
Jones, Steven J.
Marra, Marco A.
Al-Awar, Rima
Senger, Donna L.
Kaplan, David R.
Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title_full Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title_fullStr Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title_full_unstemmed Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title_short Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
title_sort small molecule epigenetic screen identifies novel ezh2 and hdac inhibitors that target glioblastoma brain tumor-initiating cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312317/
https://www.ncbi.nlm.nih.gov/pubmed/27449082
http://dx.doi.org/10.18632/oncotarget.10661
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