Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.

Abstract

e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.