Category: Drug Target Strategies
Tazemetostat (EPZ-6438) is a potent, orally bioavailable small molecule inhibitor of EZH2, the enzymatic subunit of the polycomb repressive complex 2, which is presently being evaluated in multiple phase II clinical trials for treatment of non-Hodgkin lymphoma, mesothelioma and molecularly defined solid tumors. Objective clinical responses have been reported in patients with B-cell lymphomas in phase I and in preliminary analysis of phase 2 studies of tazemetostat.
EZH2 has been shown to play a key role in the maturation of B-cells. Moreover, multiple B-cell malignancies are dependent on EZH2 for survival. Preclinical studies in multiple myeloma (MM), a disease arising from differentiated B-cell lymphocyte plasmablasts, have shown that treatment with EZH2 inhibitors elicited significant antiproliferative activity, suggesting EZH2 may be an attractive therapeutic target in this indication.
The most widely used MM treatment regimens include combinations of several Standard of Care (SOC) agents. In order to support potential future clinical scenarios with tazemetostat, we established a quantitative high-density, high-quality in vitro combination platform in 384-well format to test the anti-proliferative effects in double and triple combinations utilizing assay-ready plates prepared with nanoliter dispensing technology. A panel of eight MM cell lines with a range of common genetic alterations and with varying sensitivities to tazemetostat and SOCs were selected. Assays were conducted in two different dosing schedules: a pretreatment model, in which cells were primed with tazemetostat for seven days prior to co-treatment with a second agent and a co-treatment model in which tazemetostat and the combination partner(s) were added simultaneously for seven days. Cell viability was quantified via ATP detection with Cell-Titer Glo®. Data analysis entailed calculation of IC50/IC80 shifts from dose response curves of one compound in the presence of varying concentrations of the combination partner. Synergy quantification was done by analytical approaches including Loewe Additivity, Bliss Independence and Combination Index (CI) using Horizon’s ChaliceTM Analyzer and BiosoftTM CalcuSyn softwares.
We observed consistent synergy across the panel of cell lines when tazemetostat was combined with glucocorticoid receptor agonists and other immunomodulatory drugs. Interestingly, the triple combination of tazemetostat, dexamethasone and pomalidomide elicited a synergistic, apoptosis-driven antiproliferative effect that was greater than that seen with any dual combination of these agents. To further validate these results, we conducted in vivo studies in MM xenografts models. We observed that the combination benefit seen in vitro was recapitulated in vivo, with tumor regressions induced by triple combination treatment in two out of three models. Current efforts are underway to explore the mechanism of action behind this synergy.
Vinny Motwani– Research Associate, Epizyme, Cambridge, MA
Epizyme is a clinical stage biopharmaceutical company that is creating novel epigenetic therapies for cancer patients. I work in the position of Research Associate in Biological Sciences department in Epizyme Inc. Specifically I am involved in cell based assay development and its execution to support the in-vitro preclinical efforts across several indications during drug discovery process.I also assist in developing novel inhibitors targeting epigenetic enzymes implicated in cancer and perform mechanism of action studies on lead compounds. I received a Professional Science of Masters(PSM) degree in Biotechnology from Northeastern University,Boston in 2016 and prior to that a Bachelor of Engineering (B.E) degree from Manipal Institute of Technology, India in 2013.