Contributions
Abstract: EP859
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Tazemetostat (EZM6438) is a potent, orally bioavailable small molecule inhibitor of EZH2, the enzymatic subunit of the polycomb repressive complex 2, which has been approved for treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma. EZH2 has been shown to play a key role in B-cell maturation and multiple B-cell malignancies are dependent on EZH2 for survival. Mantle cell lymphoma (MCL) is a rare subtype of mature B cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1, which plays a significant role in tumor cell proliferation via cell cycle dysregulation, chromosomal instability and epigenetic regulation. This disease most often presents at an advanced stage and while most of the patients respond to frontline therapy (including Bruton’s Tyrosine Kinase (BTK) inhibitors) they eventually relapse. The rate of intrinsic and acquired resistance results in a high unmet medical need.
Aims
Investigate if tazemetostat, as monotherapy or in combination with standard of care (SOCs) or emerging therapies, could offer therapeutic benefit to the BTK inhibitor-resistant MCL population.
Methods
In vitro 14-day proliferation assays assessed the activity of tazemetostat in MCL cell lines. In vitro proliferation assays in a panel of MCL cell lines evaluated the combinatorial potential of tazemetostat and SOCs or emerging therapies by pre-treating cells with tazemetostat for 7 days followed by co-treatment for 7 days with tazemetostat and combination partners. In vitro 10-day assays evaluated the ex vivo effect of tazemetostat on tumor B-cell proliferation from MCL patient samples. MCL cell line murine xenograft study assessed tumor growth delay in response to treatment with tazemetostat, BTK inhibitor zanubrutinib and their combination. ELISA assessed the intratumoral levels of H3K27me3.
Results
We demonstrated that tazemetostat synergized with zanubrutinib and resensitized a subset of cell lines that were intrinsically resistant to BTK inhibitors. In vivo studies in the MCL MINO cell line-derived murine xenograft model confirmed these findings, showing a significant tumor growth delay in response to combination treatment of tazemetostat and zanubrutinib compared to the single agent treatments with concomitant decrease in intratumoral levels of H3K27me3. To understand if tazemetostat could offer therapeutic benefit in the BTK inhibitor-acquired resistant MCL population, we generated in vitro MCL models of acquired resistance to the BTK inhibitors ibrutinib and zanubrutinib. These cell lines retained the in vitro sensitivity to tazemetostat observed in the parental cell line, suggesting tazemetostat as a potential therapeutic option in the setting of acquired resistance to BTK inhibitor. In addition, synergy was observed in in vitro combination studies with tazemetostat and lenalidomide, glucocorticoid receptor agonists and venetoclax in these cell line models. Lastly, we showed that tazemetostat induced anti-proliferative effects in samples derived from MCL patients that were relapsed or refractory to one or more current standard of care agents, including the BTK inhibitor ibrutinib. Subsequent studies aim to identify the mechanisms of growth inhibition driven by tazemetostat in MCL models, sensitive and resistant to BTK inhibitors.
Conclusion
Our data suggest that tazemetostat treatment (alone or in combination with a BTK inhibitor, SOCs or emerging therapies) could be a therapeutic option in the treatment of the MCL patient population that is relapsed/refractory to BTK inhibitor therapy.
Keyword(s): EZH2, Mantle cell lymphoma, Resistance, Synergy
Abstract: EP859
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Tazemetostat (EZM6438) is a potent, orally bioavailable small molecule inhibitor of EZH2, the enzymatic subunit of the polycomb repressive complex 2, which has been approved for treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma. EZH2 has been shown to play a key role in B-cell maturation and multiple B-cell malignancies are dependent on EZH2 for survival. Mantle cell lymphoma (MCL) is a rare subtype of mature B cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1, which plays a significant role in tumor cell proliferation via cell cycle dysregulation, chromosomal instability and epigenetic regulation. This disease most often presents at an advanced stage and while most of the patients respond to frontline therapy (including Bruton’s Tyrosine Kinase (BTK) inhibitors) they eventually relapse. The rate of intrinsic and acquired resistance results in a high unmet medical need.
Aims
Investigate if tazemetostat, as monotherapy or in combination with standard of care (SOCs) or emerging therapies, could offer therapeutic benefit to the BTK inhibitor-resistant MCL population.
Methods
In vitro 14-day proliferation assays assessed the activity of tazemetostat in MCL cell lines. In vitro proliferation assays in a panel of MCL cell lines evaluated the combinatorial potential of tazemetostat and SOCs or emerging therapies by pre-treating cells with tazemetostat for 7 days followed by co-treatment for 7 days with tazemetostat and combination partners. In vitro 10-day assays evaluated the ex vivo effect of tazemetostat on tumor B-cell proliferation from MCL patient samples. MCL cell line murine xenograft study assessed tumor growth delay in response to treatment with tazemetostat, BTK inhibitor zanubrutinib and their combination. ELISA assessed the intratumoral levels of H3K27me3.
Results
We demonstrated that tazemetostat synergized with zanubrutinib and resensitized a subset of cell lines that were intrinsically resistant to BTK inhibitors. In vivo studies in the MCL MINO cell line-derived murine xenograft model confirmed these findings, showing a significant tumor growth delay in response to combination treatment of tazemetostat and zanubrutinib compared to the single agent treatments with concomitant decrease in intratumoral levels of H3K27me3. To understand if tazemetostat could offer therapeutic benefit in the BTK inhibitor-acquired resistant MCL population, we generated in vitro MCL models of acquired resistance to the BTK inhibitors ibrutinib and zanubrutinib. These cell lines retained the in vitro sensitivity to tazemetostat observed in the parental cell line, suggesting tazemetostat as a potential therapeutic option in the setting of acquired resistance to BTK inhibitor. In addition, synergy was observed in in vitro combination studies with tazemetostat and lenalidomide, glucocorticoid receptor agonists and venetoclax in these cell line models. Lastly, we showed that tazemetostat induced anti-proliferative effects in samples derived from MCL patients that were relapsed or refractory to one or more current standard of care agents, including the BTK inhibitor ibrutinib. Subsequent studies aim to identify the mechanisms of growth inhibition driven by tazemetostat in MCL models, sensitive and resistant to BTK inhibitors.
Conclusion
Our data suggest that tazemetostat treatment (alone or in combination with a BTK inhibitor, SOCs or emerging therapies) could be a therapeutic option in the treatment of the MCL patient population that is relapsed/refractory to BTK inhibitor therapy.
Keyword(s): EZH2, Mantle cell lymphoma, Resistance, Synergy