Abstract IA27: Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench

The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example, gene amplification, chromosomal translocations, point mutations and synthetic lethal relationships. The enzyme EZH2 provides a representative example of altered PMTs that act as genetic drivers of specific human cancers. Point mutations of EZH2 are found in a subset of non-Hodgkins lymphoma patients; the enzymatic activity of both wild type and mutant EZH2 are required for pathogenesis in these patients. Also, deletion of the INI1 or SMARCA4 subunit of the SWI/SNF chromatin-remodeling complex occur in a number of cancer types. For example, INI1 is deleted in nearly all malignant rhabdoid tumors (MRTs), a cancer found mainly in children that carries a particularly poor prognosis. Similarly, the SMARCA4 subunit of SWI/SNF is deleted, for example, in malignant rhabdoid tumor of the ovary (MRTO, also referred to as small cell carcinoma of the ovary hypercalcemic type), an aggressive cancer affecting young women. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the INI1 deletion. MRTs and other INI1- or SMARCA4-negative cancers therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation, and we have shown that MRT cells deficient in INI1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models. Drug discovery efforts have yielded a potent, selective inhibitor of EZH2, tazemetostat (EPZ-6438), that has now transitioned into phase 2 clinical trials. This inhibitor affects the appropriate histone methyl marks in cells, leads to selective cell killing that is dependent on genetic lesions associated with EZH2 activity and effects tumor growth inhibition in xenograft models. Combining tazemetostat with other treatment modalities for non-Hodgkins lymphoma results in dramatic synergy of anti-proliferative activity in preclinical models. Results of preclinical and phase 1 clinical studies of tazemetostat will be presented.

Citation Format: Robert A. Copeland. Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA27.