Abstract

The Emerging Translational Landscape for EPZ-6438, A Small Molecule Inhibitor of EZH2

Scott Ribich, Associate Director, Epizyme

Tazemetostat (EPZ-6438) is a small molecule inhibitor of EZH2 developed by Epizyme that is currently in early clinical development for the treatment of various cancer types. EZH2 is the catalytic subunit of PRC2 (polycomb repressive complex 2), a histone methyltransferase responsible for mono-, di, and trimethylation of H3K27, and has a well characterized role in transcriptional silencing. Dysregulation of EZH2, other PRC2 subunits, and other genes associated with the H3K27 methylation signaling axis have been associated with a diverse set of cancer indications, including subsets of non-Hodgkin lymphoma (NHL) with gain-of-function mutations in EZH2. Inhibition of H3K27Me3 with tazemetostat leads to killing of EZH2 mutant lymphoma cells. Beyond these EZH2 mutant-bearing cell lines, there is evidence that small molecule inhibitors of EZH2 also have antiproliferative activity in NHL lines with wild-type EZH2. In addition to lymphoma there is evidence that EZH2 inhibitors have therapeutic potential in solid tumor indications, including undifferentiated tumors with deficient expression of the mSWI/SNF subunits INI1 (such as Malignant Rhabdoid Tumors and Synovial Sarcoma) or certain SMARCA4 (such as Small Cell-Carcinoma of the Ovary). The properties of tazemetostat, including their ability to selectively kill tumor cells bearing specific genetic alterations in cell culture and animal models will be discussed as well as an update on the early clinical experience with tazemetostat – an EZH2 inhibitor that recently entered Phase 2 clinical testing.