Abstract 299: Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers

Abstract

Abstract Depending upon the definition used, as many as half of all cancers diagnosed are considered rare cancers, and most rare cancer patients would greatly benefit from additional therapies. Repurposing of drugs for use in oncology represents an attractive strategy for the rapid development of therapies that address the significant unmet medical need that remains for rare cancers. The FDA-approved anti-helminthic drug mebendazole (MBZ) has been reported to affect several biological pathways involved in tumor growth and metastasis. Based on this activity, multiple rare cancer tumor cell lines including neuroblastoma, carcinoid tumors, esophageal adenocarcinoma, gastrointestinal stromal tumors, leiomyosarcoma, pheochromocytoma, and mesothelioma were analyzed for their susceptibility to MBZ treatment alone or in combination with standard chemotherapeutic agents in vitro. Cultured cells exposed to increasing concentrations of MBZ alone showed a significant decrease in cell viability with IC50s ranging from 0.09-2.2 μM. To evaluate efficacy of MBZ in an additional model system, an ex vivo 3D assay using gastric cancer primary cells isolated from two patient-derived xenograft (PDX) models was performed. Cells were seeded in 3D cultures and treated for seven days with MBZ at nine different doses in triplicate. IC50s were determined to be 0.74 and 0.76 μM indicative of significant potency. These results along with the in vitro data generated using cell lines suggest that MBZ may represent an effective anti-cancer agent across multiple rare cancer indications. However, since tumor cells can often evade or develop resistance to single agent therapy, the potential for synergistic combinations with chemotherapeutic agents was also explored in vitro. Cells were plated in triplicate and treated with a range of concentrations of MBZ and relevant chemotherapeutic agents in a complete Latin square. Combination indexes (CI) were determined based on the method described by Chou and Talalay. Several synergistic drug combinations were identified with CI values ranging from 0.008 to 0.428 (CI < 0.9 indicates synergy). Overall, our results indicate that synergistic combinations of MBZ and chemotherapy agents represent a promising strategy for the treatment of rare cancers. Citation Format: Mahta Samizadeh, Debashree Chakrabarti, Yuhan Zhu, Robert Louis Treuting, Johanne Kaplan, William Siders, Jamie D. Barber. Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 299.