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Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma.


ABSTRACT: Children with ependymoma (EPN) are cured in less than 50% of cases, with little improvement in outcome over the last several decades. Chemotherapy has not affected survival in EPN, due in part to a lack of preclinical models that has precluded comprehensive drug testing. We recently developed two human EPN cell lines harboring high-risk phenotypes which provided us with an opportunity to execute translational studies. EPN and other pediatric brain tumor cell lines were subject to a large-scale comparative drug screen of FDA-approved oncology drugs for rapid clinical application. The results of this in vitro study were combined with in silico prediction of drug sensitivity to identify EPN-selective compounds, which were validated by dose curve and time course modeling. Mechanisms of EPN-selective antitumor effect were further investigated using transcriptome and proteome analyses. We identified three classes of oncology drugs that showed EPN-selective antitumor effect, namely, (i) fluorinated pyrimidines (5-fluorouracil, carmofur, and floxuridine), (ii) retinoids (bexarotene, tretinoin and isotretinoin), and (iii) a subset of small-molecule multireceptor tyrosine kinase inhibitors (axitinib, imatinib, and pazopanib). Axitinib's antitumor mechanism in EPN cell lines involved inhibition of PDGFR? and PDGFR? and was associated with reduced mitosis-related gene expression and cellular senescence. The clinically available, EPN-selective oncology drugs identified by our study have the potential to critically inform design of upcoming clinical studies in EPN, in particular for those children with recurrent EPN who are in the greatest need of novel therapeutic approaches. Mol Cancer Ther; 17(9); 1984-94. ©2018 AACR.

SUBMITTER: Donson AM 

PROVIDER: S-EPMC6125158 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma.

Donson Andrew M AM   Amani Vladimir V   Warner Elliot A EA   Griesinger Andrea M AM   Witt Davis A DA   Levy Jean M Mulcahy JMM   Hoffman Lindsey M LM   Hankinson Todd C TC   Handler Michael H MH   Vibhakar Rajeev R   Dorris Kathleen K   Foreman Nicholas K NK  

Molecular cancer therapeutics 20180620 9


Children with ependymoma (EPN) are cured in less than 50% of cases, with little improvement in outcome over the last several decades. Chemotherapy has not affected survival in EPN, due in part to a lack of preclinical models that has precluded comprehensive drug testing. We recently developed two human EPN cell lines harboring high-risk phenotypes which provided us with an opportunity to execute translational studies. EPN and other pediatric brain tumor cell lines were subject to a large-scale c  ...[more]

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