Abstract 1944: Tazemetostat displays synergistic antiproliferative activity with backbone therapies in preclinical models of AT/RT and MRT
Authors: Klaus Christine R. , Keats Jeffrey A. , Smith Jesse J. , Chesworth Richard , Copeland Robert A. , Ribich Scott , Raimondi Alejandra 
Published: July 2017

Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid Rhabdoid Tumors (AT/RT) are typically pediatric cancers which are rare and aggressive with extremely high unmet medical need. At a molecular level MRT and AT/RT tumors are almost universally characterized by loss of the INI1 protein (also known as SNF5 or SMARCB1), a component of the Switch Sucrose Non-fermentable (SWI/SNF) multimeric chromatin modifying complex. In many cell types, the SWI/SNF complex and the PRC2 complex have an antagonistic relationship in the regulation of tumor suppressor genes, cell cycle checkpoints, hedgehog and myc pathway genes, among others [Wilson et al, Cancer Cell. 2010 Oct 19;18(4):316-28.]. This explicated the possibility of a novel treatment modality for these tumors, based on inhibition of EZH2 - the catalytic subunit of PRC2. Tazemetostat (EPZ-6438) is a potent and orally bioavailable small molecule inhibitor of EZH2 currently in phase 2 clinical trials in adult patients with non-Hodgkin lymphoma, INI1-negative tumors and mesothelioma. Dependency of INI1-negative tumors on EZH2 catalytic activity was demonstrated in preclinical models of MRT, where robust tumor regressions were induced with tazemetostat treatment [Knutson et al, Proc Natl Acad Sci USA. 2013 May 7;110(19):7922-7]. Consistent with this, tazemetostat demonstrated activity in relapsed or refractory patients with INI1-negative tumors enrolled in the adult phase 1 clinical trial. In addition, a phase 1 dose escalation study in pediatric patients with INI1-negative solid tumors is currently ongoing. Backbone therapies for MRT and AT/RT are comprised of cytotoxic chemotherapy which may or may not be administered in the context of stem cell transplant, in addition to surgical resection and radiation therapy. In support of combination clinical scenarios including EZH2 inhibition in this setting, we sought to explore the antiproliferative effects of combining tazemetostat with current small molecule treatment therapies in cell line models of AT/RT and MRT. Synergistic activity was observed when tazometostat was combined with individual components of chemotherapeutic regimens and targeted therapies such as vincristine, doxorubicin, alisertib and HDAC inhibitors.Further, we investigated the effects of ionizing radiation together with tazemetostat treatment. Application of X-ray irradiation concomitantly or after tazemetostat treatment, induced robust antiproliferative activity and reduction in clonogenic potential of both AT/RT cell lines tested.Taken together these results suggest that pharmacological inhibition of EZH2 enhances the activity of backbone therapy and may have an advantage over monotherapy in INI1-negative cancers supporting the therapeutic potential of combination regimens that include tazemetostat in these tumors.

Citation Format: Christine R. Klaus, Jeffrey A. Keats, Jesse J. Smith, Richard Chesworth, Robert A. Copeland, Scott Ribich, Alejandra Raimondi. Tazemetostat displays synergistic antiproliferative activity with backbone therapies in preclinical models of AT/RT and MRT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1944. doi:10.1158/1538-7445.AM2017-1944