Figure 6: Imipridones extend host survival in patient-derived xenograft (PDX) models of GBM and reduce tumor growth synergistically with BRD4 and PHGDH inhibitors.

A, U87 GBM cells (low to intermediate c-myc levels) were implanted intracranially in nude mice. After randomization in two groups, treatment was initiated with either vehicle or ONC212 (100 mg/kg) twice a week. Primary endpoint for these experiments is survival or a moribund state of the animal. Shown are Kaplan-Meier-survival curves and the log-rank test was applied to calculate statistical significance. B, Patient-derived xenograft cells, GBM123 (high c-myc expressing tumors), were implanted intracranially in nude mice. After randomization in two groups, treatment was initiated with either vehicle or ONC212 (100 mg/kg) twice a week. Primary endpoint for these experiments is survival or a moribund state of the animal. Shown are Kaplan-Meier-survival curves and the log-rank test was applied to calculate statistical significance. C, D, E, Stem-like GBM cells, NCH644, were implanted subcutaneously. Once tumors were established, animals were randomized into four designated groups, vehicle, ONC201 (100 mg/kg), OTX015 (OTX) (75 mg/kg) or the combination of ONC201+OTX015. Treatments were given three times a week. Caliper measurements were performed and tumor volumes were calculated as previously described. At the end of the experiment, statistical analysis was performed, using the Mann-Whitney test. A p value of less than 0.05 was considered as statistical significant. Shown are scatter plots with means and SD. Gross images of the explanted tumors are provided in panel E. F, Representative histological images of the individual treatments of the xenografts performed in C. Slides were stained with hematoxylin and eosin (HE). G, U87-EGFR-vIII cells were implanted subcutaneously in nude mice. After establishment of tumors, four groups were formed as indicated: Vehicle, ONC212 (50 mg/kg), NCT-503 (50 mg/kg) or the combination of ONC212 and NCT-503. Shown are scatter plots of relative tumor fold changes in (%) with means and SD (last day of experiment; normalization is to 100% at the start of the experiment). H, HCT116 cells were implanted subcutaneously in nude mice. After establishment of tumors, four groups were formed as indicated: Vehicle, ONC212 (50 mg/kg), NCT-503 (50 mg/kg) or the combination of ONC212 and NCT-503. Shown are means and SD. I, Scatter plots of the final tumor sizes on the day of conclusion of the experiment. ** means p-value less than 0.01, whereas * indicates p of less than 0.05.