Abstract 2888: Targeting the fatal pediatric brain tumors AT/RT and DIPG with the DNA binding agent quinacrine
| Autor: | Harpreet Kaur, Huizi Guo, Peter Green, Sepehr Akhtarkhavari, Smit Shah, Charles G. Eberhart, Eric H. Raabe |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:2888-2888 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2019-2888 |
| Popis: | 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 previously shown that multiple primary brain 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 and glioma 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 ten patient-derived cell lines: five AT/RT (BT37, CHLA-05, CHLA-06, BT-12, CHLA-266) and five DIPG (JHHDIPG1, SUDIPGXIII, JHHDIPG16A, SF7761, HSJD-007). Quinacrine has been used in millions of humans to treat malaria and parasitic infections, has a well-known safety profile and can penetrate the brain. Using quinacrine fluorescence as a surrogate, we can achieve therapeutically efficacious 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 growth (MTS) and proliferation (BrdU) compared to vehicle-treated cells (P Citation Format: Harpreet Kaur, Huizi Guo, Peter Green, Sepehr Akhtarkhavari, Smit Shah, Charles G. Eberhart, Eric H. Raabe. Targeting the fatal pediatric brain tumors AT/RT and DIPG with the DNA binding agent quinacrine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2888. |
| Databáze: | OpenAIRE |
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