Abstract 1519: Cantrixil targets ovarian cancer stem cells and prevents recurrence in a cisplatin-resistant animal model

Abstract

Abstract Background: Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer (EOC) and is associated with high mortality. Growing evidence suggests that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. Current modalities are not able to target these cancer stem cells (CSC), thus there is a need to develop novel treatment approaches. We developed a library of super-benzopyran (SBP) analogues to generate potent compounds that can induce cell death in the chemoresistant CSC. We report the anti-tumoral in vivo efficacy of Cantrixil in a cisplatin-resistant animal model as monotherapy, and in combination with cisplatin. Furthermore, Cantrixil as salvage therapy prevents recurrence following paclitaxel treatment and significantly prolongs survival. Materials and methods: A panel of SPB analogues were generated and activity was determined by testing against pure clones of CD44+/MyD88+ EOC stem cells. In vitro efficacy was screened using the IncucyteTM kinetic imaging platform complemented by CelltoxTM dye labelling. In vivo efficacy and toxicology was tested using an intra-peritoneal (i.p.) cisplatin-resistant ovarian cancer xenograft model 1. Results: Cantrixil was the most potent analogue, inducing cell death in all EOC stem cell clones tested (IC50 of 136 nM). Cell death was associated with the activation of the JNK pathway, loss of mitochondrial membrane potential, and caspase activation. In vivo, Cantrixil, as mono-therapy, significantly decreased i.p. tumor burden compared to vehicle control (p = 0.0001 n = 10) while cisplatin had no effect(p = 0.8). Furthermore, the combination of Cantrixil and cisplatin significantly decreases tumor burden compared to ciplatin alone or control (p = 0.002 and p = 0.004) In addition, using an in vivo recurrent EOC model, maintenance treatment with Cantrixil given post a Paclitaxel regimen prevented recurrent disease and significantly decreased metastatic tumor burden compared to maintenance with Paclitaxel (p = 0.002). Conclusion: We described the in vivo anti-tumoral effect of a novel compound, Cantrixil, which exhibits significant efficacy against chemoresistant EOC stem cells and is able to prevent recurrence in a cisplatin-resistant in vivo model. Recurrence characterized by chemoresistance is the main cause of mortality in ovarian cancer patients. Previous studies from our laboratory have shown that conventional chemotherapy is not effective on EOC stem cells and can not prevent recurrence. Our finding that Cantrixil, by targeting CSCs, can prevent recurrence in vivo as maintenance therapy or in combination with chemotherapy, provides a new opportunity for developing a new therapeutic strategy that can help ovarian cancer patients. 1. Craveiro V, et al. Cancer Medicine. 2013;2: 751-762. Citation Format: Gil G. Mor, Eydis Lima, Natalia Sumi, Mary Pitruzzello, Yang Yang-Hartwich, David Brown, Andrew Heaton, Ayesha B. Alvero. Cantrixil targets ovarian cancer stem cells and prevents recurrence in a cisplatin-resistant animal model. [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 1519. doi:10.1158/1538-7445.AM2015-1519