Abstract 2219: Selinexor, a selective inhibitor of nuclear export (SINE) compound, shows synergistic anti-tumor activity when combined with PD-1 blockade in a mouse model of colon cancer
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 is an oral, first-in-class SINE compound that specifically binds to the primary nuclear exporter XPO1/CRM1. XPO1 exports over 200 cargos, including major tumor suppressor proteins (TSPs), leading to their functional inactivation. Inhibition of XPO1 results in nuclear retention of TSPs and restores their normal functions. Interestingly, XPO1 also mediates the export of NFAT1c, STAT1 and STAT3, which have been implicated in regulation of the inhibitory T-cell receptor PD-1 (NFAT1c, STAT3) and its ligand, PD-L1 (STAT1). Therefore, we hypothesized that selinexor treatment will result in up-regulation of PD-1 and PD-L1, making tumor cells more amenable to immunotherapy.

Methods: The effect of selinexor on PD-1 and PD-L1 gene expression was tested in human normal donor leukocytes and in tumor cells [HCT-116(colon), PC-3 (prostate) and MDA-MB-468 (breast)], respectively by quantitative PCR. A Colon26 syngeneic mouse model of CRC was generated and animals were assigned to the following treatment groups: (i) vehicle, (ii) selinexor at sub-therapeutic dose of 5 mg/kg (M/W/F), (iii) Anti PD-1 (BioXCell), 100ug biwk and (iv) selinexor + anti-PD-1 combination. Tumor growth, weight loss and signs of toxicity were monitored for 45 days. Xenografts were harvested, RNA and DNA were collected and tumors were analyzed microscopically and by immunohistochemestry (IHC).

Results: In-vitro studies showed that selinexor induces PD-1 gene expression by ∼2-fold in normal donor leukocytes as early as 4 hrs after treatment initiation and that this change is sustained for at least 24 hrs. A similar effect was measured on PD-L1 gene expression induction in HCT-116, PC-3 and MDA-MB-468 tumor cells. In-vivo, the combination was well tolerated and no weight loss or signs of toxicity were evident. Selinexor-anti-PD-1 combination therapy exhibited a synergistic effect on percent Tumor Growth Inhibition (%TGI) were the selinexor-treated group and the anti-PD-1-treated group alone were very similar with mean%TGI measuring 27% and 24% respectively, and the combination group measuring a mean%TGI of 67%. Importantly, 4-out-of-10 mice in the combination group did not have detectable tumors at day 22 and these mice were also tumor free at the end of the study, at day 45. IHC analysis showed overall enhanced effect of the combination treatment on induction of apoptosis and reduced proliferation as well as effect on specific T-cell checkpoint regulatory molecules.

Conclusion: Selinexor induces PD-1 and PD-L1 gene expression, sensitizing tumor cells to immunotherapy. Selinexor synergizes with anti-PD-1 to inhibit tumor cell proliferation and to induce apoptosis in-vivo. These data provide rational support for study of selinexor/ anti-PD-1 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 synergistic anti-tumor activity when combined with PD-1 blockade in a mouse model of colon cancer. [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 2219.