title: Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.
abstract: 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.
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: L Danielle
authors.initials: LD
authors.lastname: Johnston
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Iwanowicz
authors.affiliation: Oncology, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter-Scott
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Research and Development, Epizyme Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism; D016513:Mice, SCID; D009025:Morpholines; D009368:Neoplasm Transplantation; D011239:Prednisolone / Q000494:pharmacology; D011241:Prednisone / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D005938:Glucocorticoids; D009025:Morpholines; D011728:Pyridones; D011965:Receptors, Glucocorticoid; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C000593333:tazemetostat; D011241:Prednisone