Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.

Patients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical t...

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Main Authors: Sarah K Knutson, Natalie M Warholic, L Danielle Johnston, Christine R Klaus, Tim J Wigle, Dorothy Iwanowicz, Bruce A Littlefield, Margaret Porter-Scott, Jesse J Smith, Mikel P Moyer, Robert A Copeland, Roy M Pollock, Kevin W Kuntz, Alejandra Raimondi, Heike Keilhack
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4262195?pdf=render
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author Sarah K Knutson
Natalie M Warholic
L Danielle Johnston
Christine R Klaus
Tim J Wigle
Dorothy Iwanowicz
Bruce A Littlefield
Margaret Porter-Scott
Jesse J Smith
Mikel P Moyer
Robert A Copeland
Roy M Pollock
Kevin W Kuntz
Alejandra Raimondi
Heike Keilhack
author_facet Sarah K Knutson
Natalie M Warholic
L Danielle Johnston
Christine R Klaus
Tim J Wigle
Dorothy Iwanowicz
Bruce A Littlefield
Margaret Porter-Scott
Jesse J Smith
Mikel P Moyer
Robert A Copeland
Roy M Pollock
Kevin W Kuntz
Alejandra Raimondi
Heike Keilhack
author_sort Sarah K Knutson
collection DOAJ
description Patients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients. We report here that combining EPZ-6438 with CHOP in preclinical cell culture and mouse models results in dramatic synergy for cell killing in EZH2 mutant germinal center NHL cells. Surprisingly, we observe that much of this synergy is due to Prednisolone - a glucocorticoid receptor agonist (GRag) component of CHOP. Dramatic synergy was observed when EPZ-6438 is combined with Prednisolone alone, and a similar effect was observed with Dexamethasone, another GRag. Remarkably, the anti-proliferative effect of the EPZ-6438+GRag combination extends beyond EZH2 mutant-bearing cells to more generally impact germinal center NHL. These preclinical data reveal an unanticipated biological intersection between GR-mediated gene regulation and EZH2-mediated chromatin remodeling. The data also suggest the possibility of a significant and practical benefit of combining EZH2 inhibitors and GRag that warrants further investigation in a clinical setting.
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spelling doaj.art-4dd56e327a7d4f3e9e537bcf0baa99bb2022-12-22T02:30:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01912e11184010.1371/journal.pone.0111840Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.Sarah K KnutsonNatalie M WarholicL Danielle JohnstonChristine R KlausTim J WigleDorothy IwanowiczBruce A LittlefieldMargaret Porter-ScottJesse J SmithMikel P MoyerRobert A CopelandRoy M PollockKevin W KuntzAlejandra RaimondiHeike KeilhackPatients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients. We report here that combining EPZ-6438 with CHOP in preclinical cell culture and mouse models results in dramatic synergy for cell killing in EZH2 mutant germinal center NHL cells. Surprisingly, we observe that much of this synergy is due to Prednisolone - a glucocorticoid receptor agonist (GRag) component of CHOP. Dramatic synergy was observed when EPZ-6438 is combined with Prednisolone alone, and a similar effect was observed with Dexamethasone, another GRag. Remarkably, the anti-proliferative effect of the EPZ-6438+GRag combination extends beyond EZH2 mutant-bearing cells to more generally impact germinal center NHL. These preclinical data reveal an unanticipated biological intersection between GR-mediated gene regulation and EZH2-mediated chromatin remodeling. The data also suggest the possibility of a significant and practical benefit of combining EZH2 inhibitors and GRag that warrants further investigation in a clinical setting.http://europepmc.org/articles/PMC4262195?pdf=render
spellingShingle Sarah K Knutson
Natalie M Warholic
L Danielle Johnston
Christine R Klaus
Tim J Wigle
Dorothy Iwanowicz
Bruce A Littlefield
Margaret Porter-Scott
Jesse J Smith
Mikel P Moyer
Robert A Copeland
Roy M Pollock
Kevin W Kuntz
Alejandra Raimondi
Heike Keilhack
Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
PLoS ONE
title Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
title_full Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
title_fullStr Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
title_full_unstemmed Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
title_short Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
title_sort synergistic anti tumor activity of ezh2 inhibitors and glucocorticoid receptor agonists in models of germinal center non hodgkin lymphomas
url http://europepmc.org/articles/PMC4262195?pdf=render
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