Abstract 3488: BPM 31510 has broad utility as both a single agent and in combination with standard-of-care chemotherapy in triple-negative breast cancer

Abstract

Abstract Deregulated metabolism is recognized as a ‘hallmark of cancer’ although our understanding of the interplay between metabolic pathway activity and responses to standard-of-care chemotherapy remains limited. In vitro studies have demonstrated that BPM 31510, a Coenzyme Q10-containing proprietary formulation, alters both glycolysis and mitochondrial OXPHOS in cancer cells. Building on the clinical observation that triple-negative breast cancer (TNBC) is distinctly glycolytic compared to other breast sub-types, we examined the effects of BPM 31510 alone and in combination with standard-of-care chemotherapy in a murine xenograft model of TNBC (MDA-MB231). Tumor-bearing mice were treated with cycles of the standard ‘TAC regimen’ (5mg/kg docetaxel and 1 mg/kg doxorubicin for 3 days followed by 35 mg/kg cyclophosphamide) with or without BPM 31510 every 3 weeks. As expected, chemotherapy treatment extended survival. Notably, BPM 31510 was more effective as a single agent compared to traditional chemotherapy and extended survival by more than 6 weeks. The combination of BPM 31510 with chemotherapy further enhanced survival over either treatment regimen alone, and this was associated with attenuated tumor growth over the duration of the study. Analysis of a subset of tumors after 2 cycles of treatment confirmed a decrease in tumor weight in all treatment conditions compared to control and a significant synergistic effect of combined therapy (p = 0.02). Importantly, changes were not observed in the weight of other organs from the same mice, suggesting lack of systemic toxicity. Evidence of decreased proliferation (Ki67 staining) and enhanced caspase activity were also observed in tumors by immunohistochemical analysis. Assessment of the BPM 31510 IC50 in vitro using a panel of primary human mammary epithelial cells (HMEC), non-tumorigenic (MCF12A), and breast cancer cell lines demonstrated selective cytotoxicity in cancer cells compared to primary and non-tumorigenic cells. Moreover, MDA-MB231 was the most sensitive to BPM 31510-induced cell death in the breast cancer cell panel that was representative of multiple breast tumor sub-types. Taken together, these data demonstrate that the metabolic modulating agent BPM 31510 has broad utility as both a single agent and in combination with standard-of-care in breast cancer including distinctly glycolytic TNBC for which prognosis is poor and few therapeutic options exist. Citation Format: Niven R. Narain, Anne R. Diers, Arleide Lee, Rakibou Ouro-Djobo, Vivek K. Vishnudas, Ely Benaim, Joaquin J. Jimenez, Rangaprasad Sarangarajan. BPM 31510 has broad utility as both a single agent and in combination with standard-of-care chemotherapy in triple-negative breast cancer. [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 3488. doi:10.1158/1538-7445.AM2015-3488