Abstract 212: BPM 31510 synergizes gemcitabine efficacy in pancreatic adenocarcinoma via mechanism independent of its anti-Warburg influence on metabolism

Abstract

Abstract Pancreatic adenocarcinoma (PanCa) is associated with poor prognosis and overall survival. Current first-line therapeutics are cytotoxic agents targeting DNA based mechanistic end-points for efficacy, their use limited by dose associated toxicity. There is a critical need for therapeutics with novel mechanisms amenable to combination with current standard-of-care chemotherapy to improve outcomes. BPM 31510 is a drug that targets cellular metabolism networks, effectuating an anti-Warburg effect in cancer. The documented high metabolic phenotype observed in PanCa provided rationale for investigation of BPM 31510 alone and in combination with gemcitabine in in vitro and in vivo PanCa models. Based on BPM 31510 EC50/EC>90 values for MIA-PaCa-2 and Panc-1 PanCa cell lines in vitro, the PanCa cells were significantly more sensitive to BPM 31510 compared to fibroblasts. BPM 31510 treatment in a time- and dose-dependent manner decreased the PI- and Annexin V-negative (viable) population and a concomitant increase in the percentage of Annexin V-positive cells, with PI indicative of early and late apoptosis. The anti-cancer activity of BPM 31510 was assessed in vivo using MIA-PaCa-2 tumor-bearing immune-compromised mice. Treatment with increasing doses of BPM 31510 (0.5-50 mg/kg IP, 3X/week) significantly improved survival outcomes, with the highest dose extending median survival by more than 36 days compared to saline control. Moreover, combined treatment with BPM 31510 and gemcitabine (150 mg/kg IV, 1X/week, given on cycles, 3 weeks on 1 week) resulted in further extension of median survival over either treatment alone. The mechanistic underpinnings for the enhanced efficacy of combination treatment were explored in vitro. In MIA-PaCa-2 cells, co-treatment with BPM 31510 and gemcitabine increased indices of regulated cell death higher than observed for either treatment alone. In contrast, although treatment with either BPM 31510 or gemcitabine alone increased caspase-3 activity, co-treatment did not enhance caspase-3 activation, suggesting that BPM 31510 augments gemcitabine cytotoxicity through independent mechanisms. In fact, BPM31510, and not gemcitabine, increased the mitochondrial uncoupling efficient ratio and Stateapparent in MIA-PaCa-2 cells. Nonetheless, co-treatment with BPM 31510 and gemcitabine synergistically decreased the mitochondrial membrane potential (ΔΨm) in cells prior to cell death. Taken together, these data indicate that BPM 31510-driven bioenergetic alterations are separate from the effects of gemcitabine; however, their effects converge at the mitochondrion to dissipate ΔΨm and activate regulated cell death. The data suggests that combination of BPM 31510 with gemcitabine in pancreatic cancer will effectuate an efficacy response via independent mechanisms with improvement in therapeutic outcome. Citation Format: Tulin Dadali, Anne R. Diers, Rakib Ouro-Djobo, Justin Bourdelais, Ezer Benaim, Bianca Jambhekar, Tony E. Walshe, Vivek K. Vishnudas, Joaquin J. Jimenez, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510 synergizes gemcitabine efficacy in pancreatic adenocarcinoma via mechanism independent of its anti-Warburg influence on metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 212.