Adenoid Cystic Carcinoma (ACC) is a rare adenocarcinoma arising most commonly in the major and minor salivary glands of the head and neck. Despite a deepening understanding of the molecular events that lead to sustained tumor growth, there are currently no approved therapies for ACC or many other rare cancers. Repurposing of drugs for use in oncology is of increasing interest to promote the rapid development of new therapies and address the significant unmet medical need that remains for rare cancers. The FDA-approved anti-helminthic drug mebendazole (MBZ) has been identified as an agent that can affect several cancer relevant pathways involved in tumor growth and metastasis. Anti-tumor effects of MBZ include G2/M cell cycle arrest leading to apoptosis, inhibition of the IGF1R/AKT pathway, and induction of MYB degradation by the proteasome. Based on this biology, several rare cancer tumor cell lines including neuroblastoma, rhabdomyosarcoma and Ewing sarcoma, were analyzed for sensitivity to MBZ treatment in vitro. Cultured cells were exposed to increasing concentrations of MBZ and viability was measured after 72hours. Treatment with MBZ resulted in a significant decrease in cell viability with IC50s ranging from 0.05-1 μM suggesting that MBZ may represent a potent anti-cancer agent for several rare cancer indications. Identification of therapies for ACC has been hampered by the lack of ACC cell lines and transgenic mouse models. To circumvent these issues, in collaboration with the ACC Research Foundation, the activity of MBZ was tested in several ACC patient-derived xenograft (PDX) models. Mice were implanted subcutaneously with PDX tumors and treatment was initiated when tumors reached a size of 125-300 mm3. Mice were randomized into three treatment groups to receive daily treatment with vehicle or MBZ at either 50 or 200 mg/kg for the duration of the study. Daily oral dosing with MBZ was well tolerated with no overt toxicities. Significant anti-tumor activity was observed in 2 out of 3 ACC PDX models. In the most aggressive ACCX9 PDX model, MBZ showed statistically significant anti-tumor activity at the highest dose of 200 mg/kg resulting in a significant increase in median survival compared to vehicle-treated mice (38 vs 29.5 days respectively, p=0.0013). Inhibition of tumor growth was also observed in the less aggressive ACCX6 PDX model at both the 50 and 200 mg/kg dose levels compared to vehicle and was accompanied by an increase in median survival (95.5 and 64.5 days vs 42 days respectively; p=0.0085 and p=0.083). In the reportedly more refractory ACCX5M1 PDX model, treatment with MBZ did not inhibit tumor growth. Overall, the in vitro and in vivo results suggest that MBZ potentially represents a novel therapeutic option for the treatment of rare cancers including ACC.

Citation Format: Jamie Dempsey Barber, Mahta Samizadeh, Nannan Jia, William Siders, Johanne Kaplan. Potential of mebendazole as an anti-tumor agent for adenoid cystic carcinoma and other rare cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4801.