Abstract A38: Validation of potential therapies for treatment of fatal pediatric brain tumors DIPG and AT/RT using a novel rapid intracranial model in zebrafish

Abstract

Abstract Diffuse intrinsic pontine glioma (DIPG) and atypical teratoid/rhabdoid tumors (AT/RT) are deadly pediatric brain tumors. Developing new targets and therapeutics are urgently needed. We have previously shown that multiple primary brain tumors and cell lines express increased amounts of the epigenetic modifier and DNA binding oncoprotein high-mobility group AT-hook 2 (HMGA2). Targeting HMGA2 using short hairpins decreased AT/RT and glioma growth in xenografted mice. We hypothesized that pharmacologic inhibition of HMGA proteins using DNA minor-groove binding drugs such as quinacrine would decrease tumor growth due to displacement of HMGA proteins from DNA. Quinacrine is a safe and widely used treatment for pediatric malaria and parasitic infections. We used quinacrine in six patient-derived cell lines: three AT/RT (BT37, CHLA-05, CHLA-266) and three DIPG (JHHDIPG1, SUDIPGXIII, SF7761). Using quinacrine fluorescence as a surrogate, we can achieve micromolar concentration of quinacrine in the mouse and zebrafish brain after oral administration without overt toxicity. In both tumor cell lines, quinacrine causes a dose-dependent reduction in proliferation (BrdU) and increase in apoptosis (cleaved caspase-3 and cleaved PARP) compared to vehicle-treated cells (P<0.01). Quinacrine had no effect on growth of normal hindbrain neural stem and progenitor cells. Treatment of mice bearing ATRT flank tumors with quinacrine resulted in decreased tumor volume compared to vehicle-treated mice (P<0.05). Current mouse intracranial DIPG models can take 6-9 months due to long latency. To validate quinacrine orthotopically in DIPG, we developed a novel model in zebrafish wherein we injected fluorescent DIPG cells into the developing zebrafish blastula. Five days post injection, DIPG cells had homed to the zebrafish brain. Treatment of xenografted zebrafish with quinacrine for 48 hours decreased DIPG growth by 40% as measured by fluorescence, suggesting that minor groove binding drugs such as quinacrine are a viable treatment strategy for these tumors. Future studies are aimed at investigating the mechanism of quinacrine in these tumors. Citation Format: Harpreet Kaur, Huizi Guo, David White, Peter Green, Alara M. Hector, Sepehr Akhtarkhavari, Anukriti Bhargava, Smit Shah, Charles G. Eberhart, Jeffrey Mumm, Eric H. Raabe. Validation of potential therapies for treatment of fatal pediatric brain tumors DIPG and AT/RT using a novel rapid intracranial model in zebrafish [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A38.