Abstract 5455: Nuclear export inhibitor selinexor synergizes with proteasome inhibitor marizomib in preclinical models of glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is an aggressive brain cancer with poor prognosis and limited treatment options. Selinexor is a first-in-class oral inhibitor of Exportin 1 (XPO1/CRM1) with broad anti-cancer activities and is clinically approved to treat multiple myeloma and diffuse large B cell lymphoma. In a phase 2 study of recurrent GBM, monotherapy of selinexor demonstrated clinically relevant disease control (Lassman 2021 Clin Cancer Res). Our previous preclinical studies identified synergy between selinexor and proteasome inhibitors in GBM in vitro. Among the proteasome inhibitors tested, we chose to focus on marizomib due to its ability to cross the blood-brain-barrier, supporting its use in GBM. We tested GBM cell lines and mouse xenograft models to evaluate the anti-GBM effects of selinexor and marizomib in combination. Methods: Cytotoxic effects of selinexor and marizomib were evaluated with two GBM cell lines LN18 and U87MG. The anti-GBM effects of selinexor and marizomib were further investigated in vivo with U87MG mouse xenograft models of GBM. Female nude mice carrying U87MG subcutaneous implants were treated with vehicle, selinexor, marizomib or the combination of the two agents (six mice per treatment group). Tumor volume and body weight were monitored throughout the study. Tumor samples were collected at the end of the study for transcriptomic analysis and immunohistochemistry tests. Results: Synergistic anti-GBM effects of selinexor and marizomib were observed in both LN18 and U87MG cells in vitro. In mouse xenograft models of U87MG, tumor growth was significantly inhibited by selinexor and marizomib single agents relative to controls, at Day 15 of the study, tumor growth inhibition (TGI) was 60.0% (p=0.0009) for selinexor (10 mg/kg, once per week), 49.2% (p=0.0069) for marizomib once weekly at 75 µg/kg, and 33.1% (p=0.0991) for marizomib once every 2 weeks at 75 µg/kg. Synergistic anti-GBM effect was observed in the combination groups, with a TGI of 99.6% (p<0.0001) for selinexor with once weekly marizomib, and a TGI of 90.0% (p<0.0001) for selinexor with once every other week marizomib. Conclusions: Synergistic anti-GBM effects of selinexor and marizomib in preclinical models warrants further investigation. The synergism is likely due to enhanced inhibition of the NFκB signaling pathways as previously demonstrated for selinexor and proteasome inhibitor combination. Citation Format: Hua Chang, Leah Henegar, Christopher J. Walker, Trinayan Kashyap, Marie Maloof, Feng Wang, Kathleen Martyn, Shira Orr, Sharon Tamir, Michael G. Kauffman, Sharon Shacham, Yosef Landesman. Nuclear export inhibitor selinexor synergizes with proteasome inhibitor marizomib in preclinical models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5455.