Abstract 873: BPM 31510, a clinical stage metabolic modulator, demonstrates therapeutic efficacy in glioblastoma models of temozolomide chemo-sensitive and resistance by targeting mitochondrial function

BPM31510 is a metabolic modulating agent composed of a parenteral nanodispersion of ubidecarenone which is currently in clinical studies for glioblastoma. Glioblastoma is a highly metabolic and aggressive malignancy with limited treatment options and dismal median survival. Temozolomide (TMZ) as a first line treatment option, however, 90% of recurrent gliomas acquire TMZ chemoresistance. Recently, acquisition to TMZ resistance has been correlated to alterations in mitochondrial metabolism. Thus, in the present study we sought to investigate whether BPM31510 could elicit anti-cancer activity in TMZ naïve and TMZ-chemoresistant glioma models. In vitro, in a 2D model BPM31510 treatment demonstrated anti-cancer activity in a panel of glioma cell lines (rat C6 and human U251-MG and U87-MG), and this effect was translatable in spheroidal 3D cultures. Importantly, in an aggressive rat C6 orthotopic glioma model, treatment with BPM31510 (50mg/kg/day, b.i.d) starting between 4 and 8 days post-implantation resulted in a 32% cure rate compared to 0% in controls (P < 0.001, Fisher's exact test), demonstrating an improved survival (P < 0.01, log rank survival), despite producing a minimal change in median survival (13 vs. 12 days). A marked increase in caspase3 staining was observed in tumors from BPM31510 treated animals compared to controls assessed at a similar time point post-tumor implantation, suggesting a strong apoptotic effect of this agent in vivo. Next, BPM31510 was examined in a cellular model of acquired TMZ resistance (TMZ-R) generated by exposing parental (chemosensitive naïve) U251-MG and U87-MG cells to increasing concentrations of TMZ for 9-12 months. Similar to parental cells, BPM31510 displayed anti-cancer activity in both TMZ-R cell models, as decreased cell viability and an increase in the percentage of apoptotic cells was observed upon BPM31510 treatment. Consistent with prior studies, compared to parental cells, TMZ-R cells demonstrated metabolic rewiring characterized by increases in mitochondrial function parameters and decreased extracellular acidification rate, indicative of glycolytic flux. Regardless of chemosensitivity, BPM31510 decreased mitochondrial substrate oxidation (e.g., succinate, glycerol-3-phosphate) at doses which induce cell death. Concomitantly, increases in the reactive oxygen species production were observed with BPM 31510 treatment in both parental and TMZ-R cell lines. Together, these data define a link between regulatio