Validation of drug response of Selinexor in GBM PDX models
Glioblastoma (GBM) is one of the most aggressive forms of brain cancer, comprising 45% of all primary brain and central nervous system tumors. Currently, there is only one approved treatment for GBM, which involves temozolomide (TMZ). The treatment is only effective on a small subset of patients, with only 6.9% of patients surviving longer than 5 years after initial diagnosis, demonstrating the importance of developing alternative treatments. Selinexor has been FDA approved as an effective drug when used in combination therapies for relapsed/refractory multiple myeloma. Selinexor covalently binds to Exportin 1 (XPO1), a nuclear export protein, and compels essential tumor suppressors and pro-apoptotic factors to localize within the nucleus. 8 GBM lines were selected based upon a progression free survival (PFS) predictive model developed by Dr. Lahouel’s lab. The selected GBM models were dosed with Selinexor to determine sensitivity (drug concentration that kills half the cells, IC50). The models displayed differential sensitivity to Selinexor that did not align with predicted responses in vivo. GBM6 underwent extreme limiting dilution analysis (ELDA) to determine Selinexor’s effect on the glioma stem cell (GSC) population. Selinexor displayed a preferential effect on the GSC population of GBM6 which could translate to a greater progression free survival in vivo. Further analysis using western blotting was used to evaluate if XPO1 protein expression levels correlate with in vitro sensitivity. No correlation between XPO1 expression and in vitro sensitivity was observed, suggesting that XPO1 expression is not a signature of vulnerability to Selinexor. Differential expression (DE) analysis was performed to observe expression differences between predicted responders and non-responders as well as in vitro sensitive and resistant GBM lines. Genes identified from the DE represent potential targets for combination therapies tailored to GBM.
