Ovarian cancer is the most lethal gynecological cancer, with overall five-year survival for women with advanced disease being at only 25%. The current standard of care is treatment with a platinum-based chemotherapy drug. Unfortunately, a subpopulation of tumor cells often persists, contributing to platinum-based chemotherapy resistance and disease recurrence. In this study we investigated drugs to target these putative tumor-initiating cells (TICs), and explored the pathways of these drugs in both adherent proliferative cell culture conditions and non-adherent TIC-enriched cultures. We conducted a drug screen under both growth conditions, in order to identify compounds that are able to inhibit growth of TICs. Of the drugs identified, we focused further efforts on those involved with inhibiting the NF-kappaB pathway because prior studies have linked NF-kappaB activity with drug resistance and poor survival. Cell viability assays done with the four drugs, bardoxolone methyl, salinomycin, disulfiram, and elesclomol, show these drugs inhibit the growth of ovarian cancer cell lines both as TICs and in corresponding adherent cultures. Disulfiram showed preferential killing of TICs in some of the cell lines tested. All drugs showed some evidence for inhibiting NF-kappaB on Western blot, and ability to decrease CD133/ALDH double-positive TICs on flow cytometry. Carboplatin is known to kill proliferative ovarian cancer cells, and increase the relative percentage of CD133/ALDH positive TICs. Our ongoing studies will address combination of each drug with carboplatin, with the hypothesis that these drugs will increase in vivo efficacy by suppressing TICs, and thereby decrease recurrence of platinum-resistant ovarian cancer.
Citation Format: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata. Identifying drugs that target ovarian cancer tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2017-112