TMET-22. BPM31510 engagement of the Warburg effect in GBM to therapeutically modulate tumor metabolism through ROS mediated processes preclinically and clinically

Abstract BACKGROUND German clinician and Nobel laureate, Otto Warburg, hypothesized that carcinogenesis involves an irreversible alteration in metabolism in tumors compared to non-tumorigenic tissue. This process involves elevation of glycolysis to support tumor growth and decrease in mitochondrial function as a protective mechanism in cancer. BPM31510, a nanoparticle formulation of ubiquinone, has been evaluated in a Phase 1 high-grade glioma trial (NCT03020602) and is being developed in a Phase 2 GBM clinical trial as a priming agent (NCT04752813). METHODS Preclinical and/or clinical sample analysis was performed using 2DG-PET, metabolomics, quinomics (spatial and LC MS/MS), spatial omics analysis along with integration of The Cancer Genome Atlas Program (TCGA) analysis of ubiquinone and ROS mediated pathways. RESULTS Integrated analysis revealed that BPM31510 activates oxidative phosphorylation, increases reactive species in the tumor, and down regulates glycolysis leading to a therapeutic benefit. The delivery of therapeutically actionable levels of ubiquinone to tumor mitochondria results in a pharmacodynamic alteration in the ubiquinone biosynthetic pathway (as evidenced preclinically by increases in 4-hydroxybenzoic acid and vanillic acid). To this extent, we have expanded our translational analysis of available RNA-seq, methylation, CNV, and mutation information using TCGA dataset to determine the impact of ubiquinone biosynthesis pathway expression in cancers, most notably GBM on inducing ROS mediated cell death. Alterations in ubiquinone pathway index (UBI), even with disruption of a single gene in the pathway, is connected with increased susceptibility to mitochondrial driven ROS. CONCLUSIONS This analysis has revealed a clear impact of the ubiquinone biosynthesis pathway in cancer that can be therapeutically leveraged through the actions of BPM31510 to induce ROS leading to potentially improved clinical outcome in GBM patients.