Abstract 2428: Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients

Abstract

Abstract Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women, frequently associated with carboplatin resistance, underlining the need of more efficient and targeted therapies. F14512 is a novel concept of drug vectorization that we propose here to investigate in ovarian cancer models. F14512 is an epipodophyllotoxin-core linked to a spermine chain, which enters selectively tumor cells via the polyamine transport system (PTS), currently in clinical phase II evaluation in AML. We compared the effects of F14512 versus etoposide against OVCAR-3, IGROV-1, SKOV-3, A2780S and A2780R cancer cell lines. Using the F17073 PTS fluorescent probe, we determined the PTS activity of these cells and of 18 clinical samples. As results, F14512 displayed strong anti-proliferative and pro-apoptotic activities in carboplatin-resistant models, being increased in cell lines with high levels of PTS. Consistently, at a dose of 1.25 mg/kg, F14512 significantly inhibited tumor growth in cisplatin-resistant SKOV-3 xenograft model. Interestingly, ex vivo analysis indicated that 15 patients sample out of 18 presented a higher F17073 fluorescent probe incorporation into CD326-positive tumor cells as compared to normal cells, even in the case of 2 platinum-refractory patients. Therefore, F14512 is a targeted drug with a potent anti-tumor efficacy regardless the status of cisplatin resistance. The high PTS activity detected in fresh clinical samples highlights the potential of F14512 as a new therapy for PTS-positive and platinum resistant ovarian cancer patients. Citation Format: Benoît Thibault, Gregoire Zorza, Samuel Meignan, Nicolas Guilbaud, Christian Bailly, Jean-Pierre Delord, Bettina Couderc, Anna Kruczynski, Pierre Ferre, Jean-Philippe Annereau. Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients. [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 2428. doi:10.1158/1538-7445.AM2015-2428