Abstract 1756: Preclinical activity in non-Hodgkin's lymphoma of Selinexor, a selective inhibitor of nuclear export (SINE), is enhanced through combination with standard-of-care therapies
Authors: Azmi Asfar S. , Aboukameel Amro , Carlson Robert O. , Elloul Sivan , Shacham Sharon , Kauffman Michael , Frenkel Ran , Mohammad Ramzi M. 
Published: August 2015

Abstract
The nuclear export protein Exportin 1 (XPO1) is overexpressed in diffuse large B-cell lymphoma (DLBCL), follicular small cell cleaved Lymphoma (FSCCL) and a wide variety of other cancers, which often correlates with poor prognosis. Selinexor is an oral SINE currently in Phase 1/2 clinical testing, which targets XPO1 to induce apoptosis across a broad spectrum of tumor types. This broad action is primarily due to forced nuclear retention and reactivation of tumor suppressor proteins (TSPs), resulting in selective tumor cell death. We have previously reported anti-lymphoma activity of selinexor in murine models of DLBCL, in spontaneous canine aggressive lymphomas and in preliminary results from B-cell lymphoma patients enrolled in a Phase 1 trial of hematological malignancies. One promising finding thus far is that efficacy of selinexor appears to be independent of the presence of the mutations in MYC and BCL2/6 found in “double-hit” DLBCL, which is typically resistant to standard treatments. Here we report combination studies involving Selinexor-Dexamethasone and Selinexor-mTOR inhibitor everolimus in Non Hodgkin's lymphoma relative to front-line standard of care.
Selinexor was found to be potently cytotoxic across a broad panel of B-cell lymphoma cell lines. Furthermore, combination of selinexor with dexamethasone (Dex) or the mTOR inhibitor everolimus resulted in synergistic cytotoxicity in the WSU-DLCL2 and WSU-FSCCL cell lines. The superior cytotoxicity observed in the combination was consistent with enhanced nuclear retention of different TSPs. In WSU-DLCL2 xenografts, analogs of selinexor KPT-251 and KPT-276 showed comparable efficacy to R-CHOP and in a model of disseminated follicular lymphoma using WSU-FSCCL cells, selinexor had similar efficacy to rituximab for extending survival. The combination of selinexor and Dex or selinexor and everolimus in both xenografts are ongoing.
B-cell lymphoma cells in culture are highly sensitive to selinexor. Furthermore, combination of selinexor with Dex or everolimus is synergistically toxic to DLBCL cells. This synergism is consistent with the mechanism of action of these drugs in that both selinexor and Dex antagonize NF-κB and mTOR is an XPO1 cargo protein. The comparable in vivo activity of selinexor and related SINE compounds relative standard of care is consistent with the observations of objective responses in B-cell lymphoma patients in Phase I clinical testing. Ongoing preclinical work is designed to extend comparisons of selinexor with other standard of care and broaden the characterization of combination therapies in an effort to provide a rational basis for studying specific combinations in B-cell lymphoma clinical trials.
Citation Format: Asfar S. Azmi, Amro Aboukameel, Robert O. Carlson, Sivan Elloul, Sharon Shacham, Michael Kauffman, Ran Frenkel, Ramzi M. Mohammad. Preclinical activity in non-Hodgkin's lymphoma of Selinexor, a selective inhibitor of nuclear export (SINE), is enhanced through combination with standard-of-care therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1756. doi:10.1158/1538-7445.AM2015-1756