Abstract 4849: Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine

Abstract

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are rare, incurable, and highly proliferative pediatric brain tumors. Discovering new targets and developing novel therapeutics are urgently needed for this devastating tumor. We have previously shown that AT/RT tumors and cell lines express increased amounts of the epigenetic modifier high mobility group AT-hook 2 (HMGA2). HMGA2 is a DNA-binding oncoprotein that regulates transcription during normal embryogenesis and in cancer stem cells. Targeting HMGA2 using short hairpins significantly decreased AT/RT cell growth and increased survival of xenografted mice in our studies. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs will decrease growth of AT/RT cell lines due to displacement of HMGA proteins from the DNA. We used the minor-groove binding agent quinacrine to test our hypothesis in 3 different AT/RT cell lines (BT37, CHLA-06 and CHLA-04). Quinacrine has been used in millions of humans to treat malaria and other parasitic infections and has a well known safety profile. Quinacrine penetrates the brain, and we can achieve micromolar levels of quinacrine in brain after oral administration. Quinacrine causes a dose-dependent reduction in AT/RT cell growth (MTS assay) and proliferation (BrdU incorporation) compared to vehicle-treated cells (P<0.05). Additionally, treatment of AT/RT cells with quinacrine significantly increased apoptotic cell death (increased cleaved caspase-3 and cleaved PARP expression) in a dose-dependent manner compared to vehicle-treated cells (P<0.05). Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for AT/RT. Future studies are aimed at testing the in vivo efficacy and validating the mechanism of action of quinacrine in AT/RT. Citation Format: Harpreet Kaur, Huizi Guo, Charles G. Eberhart, Eric H. Raabe. Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine [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 4849.