Abstract 1299: Selinexor, a selective inhibitor of nuclear export (SINE) compound shows enhanced anti-tumor activity when combined with either venetoclax or bendamustine in diffuse large B cell lymphoma (DLBCL) mouse models
Authors: Elloul Sivan , Chang Hua , Klebanov Boris , Kashyap Trinayan , Werman Maxwell , Lee Margaret , Landesman Yosef , Shacham Sharon , Kauffman Michael , Friedlander Sharon Y. 
Published: July 2016

Introduction: Selinexor (sel) is a small molecule inhibitor of CRM1/XPO1, the primary nuclear exporter of over 200 proteins. As such, it affects multiple cellular pathways and has been shown to be broadly synergistic with various drugs in multiple indications. We have previously shown that sel has marked activity in double-hit DLBCL in pre-clinical models and in a small cohort of patients with heavily pre-treated relapsed / refractory double or triple-hit DLBCL. The goal of this study was to test whether combination of sel with either venetoclax (ven), a selective BCL2 inhibitor or bendamustine (benda), a DNA damaging agent, can further enhance the anti-tumor effect of sel in DLBCL.

Methods: The effects of sel, benda and ven as single agents and the effects of sel in combination with either benda or ven on cell viability were tested on DLBCL cell lines including Toledo, DoHH2 and SUDHL6 using MTT assays. Total RNA and whole protein cell lysates were extracted and analyzed by qPCR and by immunoblots, respectively. Mice were implanted with either Toledo or DoHH2 cells. Toledo inoculated mice were treated with either sel or ven alone or in combination and DoHH2 inoculated mice were treated with sel, ven or benda alone or with sel-benda or sel- ven combinations.%Tumor growth inhibition (%TGI) and overall survival were determined. Xenografts were harvested and analyzed by Immunohistochemestry (IHC).

Results: Sel-ven and sel-benda were highly effective both in-vitro and in-vivo. Using MTT assay, we showed that each of the drugs have low IC50 values (nanomolar) and they function synergistically/ additively when combined. In-vivo, in the sel-benda model, treatment with each drug showed%TGI of 37% (sel) and 86% (benda) but in combination%TGI was 107%. Western and IHC analyses showed that sel reduces the expression of key DNA Damage Response (DDR) proteins presumably disabling the cells from over coming the damage induced by benda. In the sel-ven model, in both Toledo and DoHH2 mouse models, individual drugs had little effect on%TGI (Toledo: sel 4%, ABT 28%; DoHH2: sel 37%, ABT 24%) but when combined, treatment showed a synergistic effect (Toledo: 109%; DoHH2: 93%). Moreover, combination treatment of Toledo-derived large xenografts resulted in 30% tumor volume shrinkage that was sustained until the end of the study. Interestingly, BCL2 protein levels were reduced by each drug and to a further extent in the combination-treated group suggesting that the synergistic effect is induced via BCL2.

Conclusion: Selinexor is an excellent candidate partner for combination therapies in DLBCL. It shows enhanced antitumor effect with both bendamustine and venetoclax modulating DDR and BCL2 pathway activity, respectively. These data provide rational support for study of sel-ven and sel-benda combination in clinical trials.

Citation Format: Sivan Elloul, Hua Chang, Boris Klebanov, Trinayan Kashyap, Maxwell Werman, Margaret Lee, Yosef Landesman, Sharon Shacham, Michael Kauffman, Sharon Y. Friedlander. Selinexor, a selective inhibitor of nuclear export (SINE) compound shows enhanced anti-tumor activity when combined with either venetoclax or bendamustine in diffuse large B cell lymphoma (DLBCL) mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1299.