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

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: Knutson, Sarah K., Warholic, Natalie M., Johnston, L. Danielle, Klaus, Christine R., Wigle, Tim J., Iwanowicz, Dorothy, Littlefield, Bruce A., Porter-Scott, Margaret, Smith, Jesse J., Moyer, Mikel P., Copeland, Robert A., Pollock, Roy M., Kuntz, Kevin W., Raimondi, Alejandra, Keilhack, Heike
Format: Online
Language:English
Published: Public Library of Science 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262195/
id pubmed-4262195
recordtype oai_dc
spelling pubmed-42621952014-12-15 Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas Knutson, Sarah K. Warholic, Natalie M. Johnston, L. Danielle Klaus, Christine R. Wigle, Tim J. Iwanowicz, Dorothy Littlefield, Bruce A. Porter-Scott, Margaret Smith, Jesse J. Moyer, Mikel P. Copeland, Robert A. Pollock, Roy M. Kuntz, Kevin W. Raimondi, Alejandra Keilhack, Heike Research Article 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. Public Library of Science 2014-12-10 /pmc/articles/PMC4262195/ /pubmed/25493630 http://dx.doi.org/10.1371/journal.pone.0111840 Text en © 2014 Knutson et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Knutson, Sarah K.
Warholic, Natalie M.
Johnston, L. Danielle
Klaus, Christine R.
Wigle, Tim J.
Iwanowicz, Dorothy
Littlefield, Bruce A.
Porter-Scott, Margaret
Smith, Jesse J.
Moyer, Mikel P.
Copeland, Robert A.
Pollock, Roy M.
Kuntz, Kevin W.
Raimondi, Alejandra
Keilhack, Heike
spellingShingle Knutson, Sarah K.
Warholic, Natalie M.
Johnston, L. Danielle
Klaus, Christine R.
Wigle, Tim J.
Iwanowicz, Dorothy
Littlefield, Bruce A.
Porter-Scott, Margaret
Smith, Jesse J.
Moyer, Mikel P.
Copeland, Robert A.
Pollock, Roy M.
Kuntz, Kevin W.
Raimondi, Alejandra
Keilhack, Heike
Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas
author_facet Knutson, Sarah K.
Warholic, Natalie M.
Johnston, L. Danielle
Klaus, Christine R.
Wigle, Tim J.
Iwanowicz, Dorothy
Littlefield, Bruce A.
Porter-Scott, Margaret
Smith, Jesse J.
Moyer, Mikel P.
Copeland, Robert A.
Pollock, Roy M.
Kuntz, Kevin W.
Raimondi, Alejandra
Keilhack, Heike
author_sort Knutson, Sarah K.
title 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_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_sort synergistic anti-tumor activity of ezh2 inhibitors and glucocorticoid receptor agonists in models of germinal center non-hodgkin lymphomas
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.
publisher Public Library of Science
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262195/
_version_ 1613166139048722432

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