Abstract 1946: Synergistic effects of the XPO1 inhibitor selinexor with proteasome inhibitors in pediatric high-grade glioma and diffuse intrinsic pontine glioma

Background: Pediatric high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) account for the majority of pediatric brain tumor deaths and respond poorly to chemotherapy. Selinexor, a nuclear export inhibitor, is effective against HGG and DIPG in in vitro and in vivo models, but resistance to treatment develops. We previously identified the NF-κB pathway as a likely mediator of selinexor’s activity in these tumors. NF-κB transcriptional activity is regulated by an inhibitor, IKB-α, whose levels are in turn regulated by ubiquitination and proteasomal degradation. IKB-α is a client of exportin-1 (XPO1); its nuclear levels are increased by selinexor treatment, leading to inhibition of NF-κB. We subsequently identified proteasome inhibitors as potentially synergistic with selinexor in HGG and DIPG through a screen of all FDA-approved chemotherapy agents. Proteasome inhibition has also been shown to synergize with selinexor treatment in multiple myeloma and osteosarcoma. Methods: We treated HGG cell lines (BT245 and GBM1) and DIPG cell lines (DIPG4, DIPG7 and SF7761) for five days with selinexor in combination with each of three proteasome inhibitors, bortezomib, carfilzomib and marizomib, and assayed cell viability at the conclusion of treatment. In each experiment, cells were treated with selinexor, a proteasome inhibitor, and a combination of the two drugs at several constant ratios. IC50 values were computed for each drug acting alone, and the combination index (CI) of the two drugs acting together was computed using the Chou-Talalay method. We also treated SF7761 cells with a combination of radiation (8Gy), selinexor, and a proteasome inhibitor. Results: The proteasome inhibitors had widely varying IC50 values in the cell lines treated, ranging from 1nM to 5µM. The CI for the combination of selinexor and each proteasome inhibitor was consistently less than 1 (indicating a synergistic relationship) in the cell lines tested. We found that radiation and proteasome inhibition had an antagonistic relationship (CI>1), radiation and selinexor a synergistic relationship (CI