Abstract
Cell fate decisions, such as whether to self-renew or to differentiate, are regulated in large part by epigenetic mechanisms. Dysregulation of epigenetic machinery, such as histone methyltransferases, in certain progenitor cell contexts can promote increased self-renewal, decreased differentiation and ultimately oncogenesis. For example, EZH2, the histone H3K27 methyltransferase, has been implicated in a diverse set of cancer indications. As the catalytic subunit of the polycomb repressive complex 2 (PRC2), EZH2 is responsible for the initiation of gene silencing during embryonic development and in maintenance of pluripotency in certain adult stem cell settings. On the other hand, EZH2 activity is downregulated in the majority of adult somatic cells to facilitate the expression of lineage-specific gene programs, leading to differentiation. Thus, inappropriate activation of EZH2 can contribute to oncogenic signaling by potentiating “stem-like” programs in certain contexts.
For example, during B cell maturation, EZH2 activity is critical for formation of the germinal center (GC) reaction. PRC2-mediated repression of certain target sets, such as cell cycle checkpoint genes and DNA damage response genes, allows germinal center B (GCB) cells to undergo clonal expansion and somatic hypermutation. In order for GCB cells to exit the germinal center reaction, EZH2 expression and activity must be attenuated – the failure to do so may contribute to oncogenic signaling in certain B cell lymphomas. We and others have previously reported on gain-of-function mutations in EZH2, involving residues such as Y646, A682 and A692. These lesions result in increased trimethylation of H3K27 on polycomb target genes, including those required for B cell maturation and exit from the germinal center reaction. Importantly, lymphoma cell lines bearing these mutations demonstrate robust antiproliferative phenotypes, both in culture and in subcutaneous xenograft models, in response to small molecule inhibitors of EZH2. Beyond these mutant EZH2 cell lines, there is evidence that small molecule inhibitors of EZH2 also have antiproliferative activity in GCB cell and non-GCB lymphomas with wild type (wt) EZH2. These data are consistent with the idea that EZH2 is a “lineage factor” for B cell maturation, and that certain B cell lymphomas may possibly become “addicted” to EZH2 through mechanisms other than gain-of-function mutations in said gene. In addition to these preclinical findings, a recent update from ongoing clinical trials reported objective responses to single-agent tazemetostat (an EZH2 inhibitor in clinical development) in both wild-type and mutant EZH2 non-Hodgkin lymphoma (NHL) patients.
The focus of this presentation will be the emerging translational landscape for tazemetostat (EPZ-6438), a small molecule inhibitor of EZH2, currently in phase II clinical trials for multiple oncology indications, including subsets of NHL. Data to be discussed will include preclinical efforts to understand the molecular mechanisms that determine GCB and non-GCB lymphoma response to EZH2 inhibition. Additionally, preclinical investigations evaluating the combination of tazemetostat with multiple therapeutic modalities will be presented. Finally, a brief overview of the early clinical observations of tazemetostat will be discussed.
Citation Format: Jesse J. Smith. Tazemetostat, an EZH2 inhibitor and potential therapeutic for non-Hodgkin lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA27.
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