Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone

Irfana Muqbil,Amro Aboukameel,Sivan Elloul,Robert Carlson,William Senapedis,Erkan Baloglu,Michael Kauffman,Sharon Shacham,Divaya Bhutani,Jeffrey Zonder,Asfar S Azmi,Ramzi M Mohammad

doi:10.1016/j.canlet.2016.09.016

Abstract

In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL. Combination of selinexor with DEX or EVER resulted in enhanced cytotoxicity in WSU-DLCL2 and WSU-FSCCL cells which was consistent with enhanced apoptosis. Molecular analysis showed enhancement in the activation of apoptotic signaling and down-regulation of XPO1. This enhancement is consistent with the mechanism of action of these drugs in that both selinexor and DEX antagonize NF-κB (p65) and mTOR (EVER target) is an XPO1 cargo protein. SINE compounds, KPT-251 and KPT-276, showed activities similar to CHOP (cyclophosphamide–hydroxydaunorubicin–oncovin–prednisone) regimen in subcutaneous and disseminated NHL xenograft models in vivo. In both animal models the anti-lymphoma activity of selinexor is enhanced through combination with DEX or EVER. The in vivo activity of selinexor and related SINE compounds relative to ‘standard of care’ treatment is consistent with the objective responses observed in Phase I NHL patients treated with selinexor. Our pre-clinical data provide a rational basis for testing these combinations in Phase II NHL trials.

Highlights

Non-Hodgkin lymphoma (NHL) is a heterogeneous class of hematological malignancies that display a diverse range of biological phenotypes, clinical behaviors and prognoses [1]
Selinexor enhances the activity of DEX and EVER in WSU-DLCL2 and WSU-FSCCL NHL cell lines
Given that DEX targets cell survival signals through inhibition of NF-κB [21] which in turn promotes mTOR signaling [22], we explored the consequence of the combination against two well characterized NHL cell lines, WSU-DLCL2 and WSU-FSCCL

Summary

Introduction

Non-Hodgkin lymphoma (NHL) is a heterogeneous class of hematological malignancies that display a diverse range of biological phenotypes, clinical behaviors and prognoses [1]. Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in NHL, prompting evaluation of the rapamycin-analog (rapalog) or mTOR inhibitors in multiple clinical trials [4]. These rapalogs (e.g. everolimus or EVER) show activity as single agents and are an acceptable therapeutic option especially in relapsed/refractory mantle cell lymphoma. It is likely that PI3K/AKT/mTOR inhibition will find more prominent role in NHL therapy provided a superior combination of rapalogs with other novel therapies are identified that may help to bypass the heterogeneity driven resistance mechanism of this disease [5]

Methods

Results

Conclusion