Abstract 3735: Preclinical studies of salinomycin as a therapeutic agent for pediatric high-grade glioma cancer stem cells.

Abstract

Abstract Brain tumors are the most prevalent childhood solid tumors. In the low-grade astrocytomas complete surgical resection has achieved over 90% five-year survival rate. In contrast, the aggressive anaplastic astrocytoma high-grade 3 and the fast growing glioblastoma multiforme high-grade 4 are often refractory to standard therapies; the majority of these patients at presentation are beyond cure by surgery and or radiotherapy. Emerging data substantiate the idea that a small pool of post-therapy residual cells within a tumor displaying stem-like properties is responsible for relapse. Therefore, selectively targeting these cancer stem-like cells (CSCs) may lead to advances in the treatment of these tumors. Salinomycin, an antibiotic potassium ionophore, has been shown to be highly effective against breast cancer stem cells and other malignancies; however, its potential use has not been studied in childhood astrocytomas. Recent studies indicate that salinomycin exerts its effect on components of the Wnt signaling cascade. In this study, we undertook in vitro and in vivo analyses on the effect of salinomycin on four pediatric high-grade astrocytoma cell lines, UW479 (provided by Dr. John Silber, University of Washington), SF188 (from Dr. Daphne Haas-Kogan, UCSF), SJ-GBM2, and CHLA-200 (COG Cell Culture and Xenograft Repository). Our results indicated that salinomycin was able to inhibit cellular viability in a dose-dependent manner. The soft-agar anchorage independent growth assay showed salinomycin inhibition of colony formation in 3 of the 4 cell lines tested. A decrease in the number of cycling cells (S-phase) was observed in cells treated with salinomycin. Notably, a 95% reduction in the glioma stem cells, read-out as CD133+, and impairment in the ability to form spheres (read-out as self-renewal) was observed. A xenograft mouse model was used to determine the effect of salinomycin on tumor growth in vivo and is ongoing. Salinomycin's modulation of Wnt targets measured by qRT-PCR, western blot analysis, and Bio-Plex protein assays, is in progress. Our data suggest that salinomycin could be exploited for the treatment of the aggressive form of pediatric gliomas. Citation Format: Emily S. Moses, Judy C. Chang, Jaclyn Y. Hung. Preclinical studies of salinomycin as a therapeutic agent for pediatric high-grade glioma cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3735. doi:10.1158/1538-7445.AM2013-3735