Abstract 6022: Synergistic anti-cancer effects of selinexor and bevacizumab in mouse xenograft models of glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis. It is also one of the most vascularized human tumors. The anti-angiogenesis agent bevacizumab (BEV) is the only US FDA approved agent for recurrent GBM. Given the high resistance of GBM to current therapies and the failure of BEV to prolong overall survival, new therapeutic agents are in urgent need. Selinexor is a first-in-class oral inhibitor of nuclear export protein Exportin 1 (XPO1/CRM1), it readily crosses the blood-brain-barrier and demonstrates anti-cancer activity in various hematological and solid tumors. Selinexor can attenuate multiple cancer hallmarks simultaneously, anti-angiogenesis is one of the many anti-cancer mechanisms that selinexor has. In a phase 2 clinical trial of recurrent GBM, selinexor monotherapy demonstrated clinically relevant disease control with manageable side effects (Lassman 2021 Clin Cancer Res). We tested mouse xenograft models of GBM to evaluate the anti-GBM effects of selinexor and BEV. Methods: Thirty-two female nude mice with subcutaneously implanted U87MG xenografts were allocated to four treatment groups of eight mice: vehicle control, selinexor, BEV, and the selinexor and BEV combination. Selinexor was given via oral gavage at 15 mg/kg once a week on Mondays, and BEV was given at 2.5 mg/kg via intraperitoneal injection every three days, starting on Monday, for four weeks. Tumor volume and body weight of test mice were monitored throughout the experiment. Xenograft tumor samples were collected at the end of the study for gene expression analysis and immunohistochemistry tests. Results: Selinexor and BEV significantly inhibited tumor growth as single agents relative to controls, at Day 26, tumor growth inhibition (TGI) of 54.1% (p<0.0001) and 64.0% (p<0.0001), respectively. The combination of the two agents almost completely inhibited tumor growth, with a TGI of 95% (p<0.0001). Gene expression analysis showed that genes involved in angiogenesis were significantly downregulated in tumor samples collected from mice treated with both agents and was more significant than in animals treated with BEV alone. Conclusions: Synergistic anti-GBM effects of selinexor and BEV are likely due to the enhanced inhibition of angiogenesis related genes. An ongoing GBM clinical trial (XPORT-GBM-029, NCT04421378) is investigating the therapeutic efficacy of selinexor and BEV combination. Citation Format: Leah Henegar, Hua Chang, Christopher J. Walker, Trinayan Kashyap, Marie Maloof, Feng Wang, Kathleen Martyn, Shira Orr, Sharon Tamir, Michael G. Kauffman, Sharon Shacham, Yosef Landesman. Synergistic anti-cancer effects of selinexor and bevacizumab in mouse xenograft 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 6022.