Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases.
Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases.
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DOI：
10.1158/0008-5472.can-12-4258
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发表时间：
2013-10-15
期刊：
影响因子：
11.2
通讯作者：
Wechsler-Reya RJ
中科院分区：
文献类型：
--
作者：
Markant SL;Esparza LA;Sun J;Barton KL;McCoig LM;Grant GA;Crawford JR;Levy ML;Northcott PA;Shih D;Remke M;Taylor MD;Wechsler-Reya RJ
髓母细胞瘤是儿童最常见的恶性脑肿瘤。虽然积极的手术，放疗和化疗改善了预后，但幸存者遭受严重的长期副作用，许多患者仍然死于疾病。对于肿瘤由Sonic hedgehog（SHH）通路突变驱动的患者，SHH拮抗剂提供了一些希望。然而，许多SHH相关的MB对这些药物没有反应，而那些反应可能会产生耐药性。因此，SHH和非SHH相关MB都需要更有效的治疗策略。其中一种策略涉及靶向对维持肿瘤生长至关重要的细胞，称为肿瘤增殖细胞（TPC）。我们以前确定了一个群体的TPC的肿瘤补丁突变小鼠，一个模型SHH依赖性MB。这些细胞表达表面抗原CD 15/SSEA-1，并具有与细胞周期的G2/M期相关的基因水平升高。在这里，我们表明，CD 15+细胞的进展更快，通过细胞周期比CD 15-细胞，并包含在G2/M细胞的比例增加，这表明他们可能是脆弱的抑制剂，这一阶段。事实上，将肿瘤细胞暴露于Aurora和Polo样激酶（G2/M的关键调节剂）的抑制剂诱导细胞周期停滞、凋亡和对常规化疗的敏感性增强。此外，用这些药物治疗荷瘤小鼠可显著抑制肿瘤进展。重要的是，来自人类患者来源的MB异种移植物的细胞也对Aurora和Polo样激酶抑制剂敏感。我们的研究结果表明，靶向G2/M调节剂可能代表了一种治疗人类MB的新方法。
Medulloblastoma (MB) is the most common malignant brain tumor in children. While aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the Sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated MBs do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated MB. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent MB. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2/M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15- cells and contain an increased proportion of cells in G2/M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for treatment of human MB.