Abstract C117: BPM 31510 enhances efficacy of gemcitabine through orthogonal mechanisms in a preclinical model of pancreatic adenocarcinoma

Abstract Despite global advances in cancer detection and treatment in some indications, the early diagnosis and overall survival rate for pancreatic cancer (PanCa) remains dismal. Thus, there is a critical need for novel therapeutics that may combine well with standard-of-care therapy or work through novel mechanisms. Given that most pancreatic tumors exhibit a highly metabolic phenotype, we examined the effects of BPM 31510 employing in vitro and in vivo PanCa models. BPM 31510 is a metabolic-modulating agent that reverses the Warburg effect and is currently in clinical development for solid tumors alone and in combination with chemotherapy. Determination of BPM 31510 IC50 values in vitro demonstrated the PanCa cell lines MIA PaCa-2 and Panc-1 cells were significantly more sensitive to BPM 31510 (IC50 = 137 and 455 μM, respectively) compared to primary fibroblasts (IC50 = 1537 μM). IC50 and IC90 doses of BPM 31510 also decreased the viable cell population while concomitantly increasing Annexin V- and PI-positive populations in both PanCa cell types, indicating BPM 31510 induces programmed cell death. Furthermore, in combination with gemcitabine (0.1-5 μM), BPM 31510 (100 μM) decreased cell viability by more than 75% compared to either treatment alone. In vivo, treatment of MIA PaCa-2 tumor-bearing mice with increasing doses of BPM 31510 (0.5-50 mg/kg IP, 3X/week) significantly improved median survival in a dose-dependent manner, with the highest dose extending median survival by more than 36 days compared to saline control. Moreover, while median survival of MIA PaCa-2 tumor-bearing mice treated with BPM 31510 (50 mg/kg IP, 1X/day) or gemcitabine (150 mg/kg IV, 1X/week, given on cycles, 3 weeks on 1 week) monotherapy was 77 and 63 days, respectively, combination treatment resulted in median survival improvement to 113.5 days. Examination of alternative dosing regimens revealed that more frequent dosing of BPM 31510 (2X or 3X/day) alone and in combination with gemcitabine further extended median survival in this model. The preliminary mechanistic insight into additive efficacy of combination treatment was explored in vitro. BPM 31510 treatment alone significantly altered multiple aspects of mitochondrial function in MIA PaCa-2 cells, indicating that BPM 31510-driven bioenergetic alterations are separate from the effects of gemcitabine. Hence, these data demonstrate that BPM 31510 has a potent anti-cancer activity alone and in combination with standard-of-care chemotherapy in preclinical PanCa models. Citation Format: Tulin Dadali, Anne R. Diers, Arleide Lee, Rakibou Ouro-Djobo, Justin Bourdelais, Ezer Benaim, Bianca Jambhekar, Tony E. Walshe, Joaquin J. Jimenez, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510 enhances efficacy of gemcitabine through orthogonal mechanisms in a preclinical model of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C117.</jats:p

Identification of Filamin-A and -B as potential biomarkers for prostate cancer

AIM: A novel strategy for prostate cancer (PrCa) biomarker discovery is described. MATERIALS & METHODS: In vitro perturbation biology, proteomics and Bayesian causal analysis identified biomarkers that were validated in in vitro models and clinical specimens. RESULTS: Filamin-B (FLNB) and Keratin-19 were identified as biomarkers. Filamin-A (FLNA) was found to be causally linked to FLNB. Characterization of the biomarkers in a panel of cells revealed differential mRNA expression and regulation. Moreover, FLNA and FLNB were detected in the conditioned media of cells. Last, in patients without PrCa, FLNA and FLNB blood levels were positively correlated, while in patients with adenocarcinoma the relationship is dysregulated. CONCLUSION: These data support the strategy and the potential use of the biomarkers for PrCa