Abstract 3608: BPM31510 exploits differential redox vulnerabilities between normal and glioblastoma cells to mediate its anti-cancer effect

Abstract

Glioblastoma is an aggressive cancer, the proliferative capacity of which is correlated with glycolytic metabolism. BPM31510 is a novel formulation for delivery of supraphysiological levels of ubidecarenone to the mitochondria, enabling cancer specific metabolic switches. It is being studied in Phase I clinical trials versus a number of tumors, including glioma. Here, the effects of ubidecarenone on viability and redox homeostasis of glioma and non-tumorigenic cells was assessed using in vitro monoculture and coculture systems and an in vivo preclinical model. BPM31510 administration (50 mg/kg bid i.p., beginning 4-8 days post-inoculation) resulted in over a 20% long term survival rate in C6 tumor-bearing rats. We next compared BPM31510 effects in vitro between glioma lines (rat C6, human U251) and murine NIH3T3 fibroblasts, as a stromal control. In monocultures, decreased growth was observed in glioma lines and NIH3T3 with increasing BPM31510 doses; however, glioma lines were 2-fold more sensitive to BPM31510 compared to NIH3T3 cells (IC50 glioma lines: 230 µM vs IC50 NIH3T3: >460 µM). To investigate the differential sensitivity to BPM31510, a coculture system was developed by coincubating 2 x 105 C6-GFP labeled cells and NIH3T3 cells. After 6 days of coculture, the percentage of C6 relative to NIH3T3 cells was lowest at doses of BPM31510 between 115 µM and 230 µM, evidence of greater sensitivity to BPM31510-induced cytotoxicity in the C6 glioma cells than the non-tumorigenic component. At higher doses, differential effects on cell viability were less apparent. The level of superoxide, a central reactive oxygen species important in redox homeostasis, was also assessed using Mitosox in cocultures. At a BPM31510 dose which resulted in maximal differential viability between C6 and NIH3T3 cells (230 μM), the maximal differential superoxide level was likewise greatest. The basal differential in Mitosox signal was 9-fold between C6 and NIH3T3 cells, and it increased to over 50-fold upon treatment with BPM31510 (230 μM), implying that BPM31510 exploits differential redox vulnerabilities between C6 and NIH3T3 to mediate its anti-cancer activity. At high doses of BPM31510, differential effects on superoxide levels were less apparent. In summary, BPM31510 has marked anti-cancer activity in rats implanted with C6 glioma, and its differential effects on the viability of normal and transformed cells are associated with maximal differences in BPM31510-induced superoxide production. Together, these data suggest that differential redox vulnerabilities between tumorigenic and non-tumorigenic cells may underpin the anti-cancer activity of BPM31510, and identification of in vivo correlates of redox indices may represent an avenue to improved measurement of anti-cancer efficacy as well as define patient populations responsive to BPM31510. Citation Format: Jiaxin Sun, Seema Nagpal, Chirag Patel, Milton Merchant, Tiachang Jang, Anne R. Diers, Shiva Kazerounian, Stephane Gesta, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510 exploits differential redox vulnerabilities between normal and glioblastoma cells to mediate its anti-cancer effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3608.