EZH2 Inhibitor EPZ-6438 Synergizes With Anti-Lymphoma Therapies In Preclinical Models
Authors: Johnston L. Danielle , Knutson Sarah , Warholic Natalie , Klaus Christine R , Wigle Tim J. , Iwanowicz Dorothy , Littlefield Bruce A. , Scott Margaret Porter , Smith Jesse J , Moyer Mikel P , Copeland Robert A. , Pollock Roy M. , Kuntz Kevin W , Keilhack Heike , Raimondi Alejandra 
Published: October 2019

Preclinical data have suggested that small molecule inhibitors for the histone methyltransferase EZH2 represent potential new treatment modalities for Non-Hodgkin lymphomas (NHL) expressing EZH2 change of function mutations. Our group has previously reported that selective inhibition of EZH2 results in specific killing of lymphoma cells bearing EZH2 mutations in vitro and in vivo, with minimal effects on non-mutant lymphoma cells [Knutson et al. Nature Chemical Biology 2012; Keilhack et al. Blood (ASH Annual Meeting Abstracts) 2012, 120, Abstract 3712]. Since epigenetic changes have been suggested to be involved in resistance of cancer cells to many anticancer agents, we studied EPZ-6438 (or E7438), our clinical stage EZH2 inhibitor, in combination with standard of care agents for NHL, second line therapies or targeted therapies that are being explored in this indication. With continuous exposure to EPZ-6438, cell-based assays of two different EZH2 mutant cell lines demonstrated combination benefits with all components of the CHOP chemotherapy regime, second line therapies but also with several targeted therapies (for instance other epigenetic drugs, PI3K pathway or other inhibitors). These effects were not observed in an EZH2 wild type lymphoma cell line of the activated B cell type. Strong combination benefit with CHOP was also observed in two different EZH2 mutant xenograft models. For instance, in the SUDHL6 Y646N xenograft model neither EPZ-6438 nor CHOP chemotherapy alone induced a significant antitumor effect, yet their combination produced durable tumor regressions even after cessation of dosing (figure 1). Importantly, this effect was preserved when doxorubicin was omitted from the CHOP chemotherapy regime in a third study with another EZH2 mutant xenograft model. Subsequently we showed that glucocorticoid receptor agonism may be a key mechanism of the combination benefit observed with CHOP, as the antiproliferative effect of EPZ-6438 was enhanced by either prednisolone or dexamethasone alone, in several EZH2 mutant lymphoma cell lines (in vitro). Taken together these data suggest that the single agent activity of EPZ-6438 in EZH2 mutant NHL may be further enhanced and expanded through rational combination strategies.

Disclosures:

Johnston: Epizyme: Employment, Equity Ownership, stock options Other. Knutson:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, stock options Other. Warholic:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, stock options Other. Klaus:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, Stock Options Other. Wigle:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, stock options Other. Iwanowicz:Epizyme, Inc.: Employment, Equity Ownership, stock options Other. Littlefield:Eisai Inc.: Employment. Porter Scott:Epizyme, Inc: Employment, Equity Ownership, Patents & Royalties, Stock Options Other. Smith:Epizyme, Inc.: Employment, Equity Ownership, Stock Options Other. Moyer:Epizyme, Inc.: Employment, Equity Ownership, Stock Options Other. Copeland:Epizyme Inc. : Employment, Equity Ownership, Patents & Royalties, stock options Other; Mersana: Membership on an entity’s Board of Directors or advisory committees. Pollock:Epizyme Inc.: Employment, Equity Ownership, Patents & Royalties, Stock Options Other. Kuntz:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, stock options Other. Keilhack:Epizyme, Inc.: Employment, Equity Ownership, Patents & Royalties, stock options Other. Raimondi:Epizyme, Inc: Employment, Equity Ownership, Patents & Royalties, stock options Other.