ATRT-33. TARGETING THE LETHAL PEDIATRIC TUMORS ATRT AND DIPG WITH THE DNA MINOR-GROOVE BINDING AGENT QUINACRINE. Issue 2 (22nd June 2018) - Kaur, Harpreet
Abstract: Atypical teratoid/rhabdoid tumors (AT/RT) and diffuse intrinsic pontine glioma (DIPG) are incurable pediatric brain tumors. Developing new targets and novel therapeutics are urgently needed. We have shown that AT/RT and DIPG 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 growth and increased survival of xenografted mice. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs like quinacrine will decrease AT/RT and DIPG growth due to displacement of HMGA proteins from the DNA. We used quinacrine in three AT/RT (BT37, CHLA-06, CHLA-04) and DIPG (JHHDIPG1, SUDIPGXIII, JHHDIPG16A) lines. Quinacrine has been used in millions of humans to treat malaria and parasitic infections and has a well-known safety profile. Quinacrine penetrates the brain, and we can achieve micromolar levels in brain after oral administration. In both tumor cell lines, quinacrine causes a dose-dependent reduction in growth (MTS) and proliferation (BrdU) compared to vehicle-treated cells (P<0.05). Treatment of both tumor lines with quinacrine significantly increased apoptosis (cleaved caspase-3 and cleaved PARP) compared to control cells (P<0.05). Quinacrine had no effect on growth of normal hindbrain cells. Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for these devastating tumors. Future studies are aimed at validating the in vivo efficacy and mechanism of quinacrine in AT/RT and DIPG.