Abstract 3051: Functional bioenergetic signature predicts therapeutic responses to BPM 31510
Authors: Anne R. Diers, Michael A. Kiebish, Arleide Lee, Rakibou Ouro-Djobo, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain
Journal: Cancer Research (2015)

Abstract Unlike personalized strategies to target actionable gene mutations, predicting patient responses to metabolism-targeted therapies requires a phenomic - as opposed to genomic - approach to patient stratification. BPM 31510 is a propriety, ubidecarenone-containing formulation that alters mitochondrial bioenergetics and is currently in clinical trials for treatment of solid tumors. Here, we sought to identify a functional bioenergetic signature which predicts therapeutic responses to BPM 31510 using an in vitro pan-cancer model. BPM 31510 displayed anti-cancer activity across a range of cancer cell lines including those derived from breast, prostate, pancreatic, and hepatocellular carcinoma tumors with IC50 values in the μM range (137-922 μM) comparable to circulating levels achieved in clinical trial patients. For each anatomical site, selective cytotoxicity was observed in cancer cell lines compared to their respective non-tumorigenic controls. Whether mutational status is associated with response to BPM 31510 was assessed using hybrid capture sequencing data from the publically-available Cancer Cell Line Encyclopedia; however, a lack of correlation was observed across all 50 ‘driver’ mutations assessed including TP53 (breast), ETV1 (prostate), and KRAS (pancreatic). In addition, sensitivity to BPM 31510 was not correlated with proliferation rate (R2 = 0.0005), in contrast to the well-established relationship for many standard-of-care chemotherapeutic agents, suggesting that sensitivity to BPM 31510 is governed by alternative mechanisms. Using whole-cell integrated energy metabolism parameters coupled with mitochondrial substrate-level oxidation measurements, we identified cancer cell types with high glycolytic flux and low mitochondrial respiration as particularly sensitive to BPM 31510-induced cell death (R2 = 0.6140 and 0.9557, respectively). Moreover, assessment of substrate-specific oxidation of mitochondrial substrates (e.g., pyruvate, glutamate, succinate, palmitoyl carnitine, β-hydroxy-butyrate) and subsequent bioinformatics analysis revealed additional stratification parameters and a predictive functional bioenergetic signature for therapeutic responses to BPM 31510. Taken together, these data demonstrate that the anti-cancer effects of BPM 31510 are not governed by mutational status, nor proliferative capacity, but instead are dictated by the functional bioenergetic status of cancer cells. Our findings also highlight the importance of phenotypic stratification approaches to complement those at the level of the genome, particularly in the setting of anti-metabolic cancer therapies. Citation Format: Anne R. Diers, Michael A. Kiebish, Arleide Lee, Rakibou Ouro-Djobo, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. Functional bioenergetic signature predicts therapeutic responses to BPM 31510. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3051. doi:10.1158/1538-7445.AM2015-3051