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Identification of FDA-approved oncology drugs with selective potency in high-risk childhood ependymoma
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-06-20 , DOI: 10.1158/1535-7163.mct-17-1185
Andrew M. Donson 1, 2 , Vladimir Amani 1, 2 , Elliot A. Warner 1 , Andrea M. Griesinger 1, 2 , Davis A. Witt 1, 2 , Jean M. Mulcahy Levy 1, 2 , Lindsey M. Hoffman 1, 2 , Todd C. Hankinson 2, 3 , Michael H. Handler 2, 3 , Rajeev Vibhakar 1, 2 , Kathleen Dorris 1, 2 , Nicholas K. Foreman 1, 2, 3
Affiliation  

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 PDGFRα and PDGFRβ 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.

中文翻译:

鉴定 FDA 批准的对高危儿童室管膜瘤具有选择性效力的肿瘤药物

患有室管膜瘤 (EPN) 的儿童在不到 50% 的病例中被治愈,在过去的几十年里,结果几乎没有改善。化疗并未影响 EPN 的生存率,部分原因是缺乏临床前模型,无法进行全面的药物测试。我们最近开发了两种具有高风险表型的人类 EPN 细胞系,这为我们提供了进行转化研究的机会。EPN 和其他儿科脑肿瘤细胞系接受了 FDA 批准的肿瘤药物的大规模比较药物筛​​选,以便快速临床应用。这项体外研究的结果与药物敏感性的计算机预测相结合,以确定 EPN 选择性化合物,并通过剂量曲线和时间进程模型进行验证。使用转录组和蛋白质组分析进一步研究了 EPN 选择性抗肿瘤作用的机制。我们确定了三类显示 EPN 选择性抗肿瘤作用的肿瘤药物,即(i)氟化嘧啶(5-氟尿嘧啶、卡莫氟和氟尿苷),(ii)类视黄醇(贝沙罗汀、维甲酸和异维A酸),以及(iii)a小分子多受体酪氨酸激酶抑制剂(阿西替尼、伊马替尼和帕唑帕尼)的子集。阿昔替尼在 EPN 细胞系中的抗肿瘤机制涉及抑制 PDGFRα 和 PDGFRβ,并与有丝分裂相关基因表达减少和细胞衰老有关。我们的研究确定的临床可用的 EPN 选择性肿瘤药物有可能为即将进行的 EPN 临床研究的设计提供重要信息,特别是对于那些最需要新治疗方法的复发性 EPN 儿童。摩尔癌症治疗; 17(9); 1984-94。©2018 AACR。
更新日期:2018-06-20
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