Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Mol Cancer Ther; 17(7); 1405–15. ©2018 AACR.

中文翻译：

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抗癌化合物的高内涵筛选表明多酪氨酸激酶抑制剂普纳替尼可用于神经母细胞瘤治疗

在神经母细胞瘤 (NB) 中发现了新的可药物靶点，为更有效的治疗铺平了道路。然而，患有高风险 NB 的儿童仍然表现出高死亡率，促使人们寻找新的治疗选择。在这里，我们旨在通过对 349 种抗癌化合物库进行高内涵筛选，重新利用 FDA 批准的药物用于 NB 治疗。在初步筛选中，我们采用了三个 NB 细胞系，它们生长为三维 (3D) 多细胞球体，用 10 μmol/L 的文库化合物处理 72 小时。使用高内涵成像方法评估了 3D 球体的生存能力，产生了 193 种化合物的主要命中列表。我们选择了 60 个 FDA 批准的分子并优先考虑具有多靶点活性的药物，丢弃那些已经用于 NB 治疗或参加 NB 临床试验的药物。因此，进一步测试了 20 种药物在二维和 3D 模型中抑制 NB 细胞活力的功效。然后用关于副作用、治疗指数和分子靶点的数据补充剂量反应曲线，表明两种多酪氨酸激酶抑制剂，ponatinib 和 axitinib，作为在 NB 中重新定位的有希望的候选者。事实上，这两种药物都显示出诱导细胞周期阻滞和细胞凋亡，以及抑制集落形成。然而，只有普纳替尼持续影响迁移并抑制 NB 细胞的侵袭。最后，ponatinib 还证明了对原位 NB 小鼠肿瘤生长的有效抑制，为其在 NB 治疗中重新利用提供了基本原理。摩尔癌症治疗; 17(7); 1405-15。©2018 AACR。