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• W1991603322 abstract "Ependymomas are rare brain tumors that are incurable unless completely excised. The low incidence of the disease and lack of pre-clinical models has limited research efforts to advance understanding of biology and treatment. Recently, we used interspecies genomics to match specific driver mutations with distinct types of mouse neural stem cell (NSC) to accurately model human ependymoma. Here we report the use of these models for high throughput drug screening (HTS). Stem-like mouse ependymoma cells (mEPCs), non-ependymoma mouse brain tumor cells (mBTCs) and control transduced NSCs (mNSCs) were cultured in neurosphere conditions adapted for use in an automated small molecule HTS. We first performed replicate primary screens of 7,579 agents drawn from a bioactive library, FDA approved drug library and kinase library. Primary screens were conducted in a single concentration format (10µM). The primary screen was highly reproducible and ROC analysis of primary screen data was used to assess predictive power of the screen (ROC AUC>0.89 (0.85-0.92 95% CI)). A total of 602 compounds representing diverse drug classes progressed from primary to secondary screening. These included full 10-point dose response assays that identified a total of 181 agents with activity in at least one cell population. In all, 2.3% of compounds displayed anti-mEPC activity and were enriched for anti-cancer drugs (Fishers Exact P=1.9 × 10-7: Bonferroni correction threshold, p=0.0016). Since our HTS strategy included non-ependymoma tumor cells and mNSCs, we were able to refine our classification of activity to define compounds more active against mEPCs than other cells (0.08%); equally active against mEPCs and mBTCs relative to mNSCs (0.04%); equally active against all four cell types (2.2%); more active against mBTCs relative to all other cells (0.2%); more active against mNSCs relative to tumor cells (0.8%); inactive against mEPCs relative to all other cells (0.1%); and inactive against all four cell types (96%). Interestingly, anticancer compounds displayed patterns of cell-selective activity that varied according to their mechanism of action with some drug classes appearing significantly more toxic to mNSCs than either mEPCs or mBTCs. These HTS studies identified treatments for ependymoma including drugs that were relatively non-toxic to normal NSCs. Five agents were selected for assessment of in vivo against the originating ependymoma mouse models. Using the xenogen system to monitor tumor growth and assessing animal survival, we identified FDA-approved agents with activity in ependymoma which have not previously been implicated in the disease, and may be translated directly into the clinic. In summary, this approach identified a number of potential new treatments with potent activity against ependymoma relative to normal NSCs, and could be used to develop effective therapies for other rare cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4759. doi:10.1158/1538-7445.AM2011-4759" @default.
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• W1991603322 date "2011-04-15" @default.
• W1991603322 modified "2023-09-27" @default.
• W1991603322 title "Abstract 4759: Integrated in vitro and in vivo screening of tumor and normal neural stem cells identifies potential new treatments of ependymoma" @default.
• W1991603322 doi "https://doi.org/10.1158/1538-7445.am2011-4759" @default.
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