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

PLoS One. 2014 Dec 10;9(12):e111840. doi: 10.1371/journal.pone.0111840. eCollection 2014.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cyclophosphamide / pharmacology
  • Dexamethasone / pharmacology
  • Doxorubicin / pharmacology
  • Drug Evaluation, Preclinical
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucocorticoids / pharmacology
  • Humans
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / metabolism
  • Mice, SCID
  • Neoplasm Transplantation
  • Prednisolone / pharmacology
  • Prednisone / pharmacology
  • Pyridones / pharmacology*
  • Random Allocation
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism
  • Vincristine / pharmacology

Substances

  • Antineoplastic Agents
  • Benzamides
  • Glucocorticoids
  • Pyridones
  • Receptors, Glucocorticoid
  • Vincristine
  • Dexamethasone
  • Doxorubicin
  • Cyclophosphamide
  • Prednisolone
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • tazemetostat
  • Prednisone

Supplementary concepts

  • CHOP protocol

Grant support

This work was funded by Eisai Inc. through collaboration between Epizyme and Eisai. The funding entity had no input in study design, data collection and analysis and decision to publish. The funders were not involved in the preparation of the manuscript, but did review and approve it.