ATM as target for malignant glioma radiosensitization.

摘要多形性胶质母细胞瘤是一种毁灭性的脑癌，平均生存期只有12个月，而且很少。 治疗选择。因此，迫切需要更有效的治疗方法。共济失调毛细血管扩张症(A-T)突变 (ATM)是一种关键的基因组监控蛋白，它调节包括细胞在内的许多DNA损伤反应 周期检查点、DNA修复和细胞凋亡。人们认为自动取款机还起到了调节 对有丝分裂原和包括胰岛素在内的生长因子的反应，并作为细胞的主要调节因子 动态平衡。由于A-T细胞对辐射的极端敏感性，ATM的抑制剂将是很有吸引力的 GBM和其他类型癌症的放射增敏剂。近年来，以PI3K为基础的小分子抑制剂 抑制剂LY294002是由kudos制药有限公司开发的，专门针对ATM激酶。 这些抑制剂在纳摩尔到微摩尔范围内有效，并对各种人类肿瘤具有放射增敏作用。 体外培养的细胞系。我们最近证明，这些抑制剂也能抑制DNA双链断裂。 (DSB)修理。在此，第二代衍生产品KU-60019在有效和广泛使用的基础上 前身KU-55933将在体外和体内进行测试，以确定它是否会安全有效 GBM放射增敏剂。最初的实验将使用大脑器官型切片培养来表征这种效果 KU-60019对各种辐射反应的影响以及正常大脑及其不同类型细胞和 肿瘤细胞受到不同程度的影响。将特别注意KU-60019可能产生的不良影响 神经干细胞和祖细胞。然后，对KU-60019作为人体放射增敏剂进行了评价 在裸鼠体内生长的原位GBM移植将通过非侵入性生物发光和 荧光成像。我们预计将确定KU-60019是否会是一种安全有效的 GBM放射增敏剂。我们还希望为体内小鼠模型系统奠定基础 将使我们能够研究神经干细胞和祖细胞的基本放射生物学特性 评估他们对KU-60019治疗的行为和反应。

Glioblastoma multiforme (GBM) is devastating brain cancer with a mean survival of only 12 months and few therapeutic options. Thus, more effective treatment is urgently needed. Ataxia telangiectasia (A-T) mutated (ATM) is a critical genome surveillance protein that regulates many DNA damage responses including cell cycle checkpoints, DNA repair, and apoptosis. It is believed that ATM also plays additional roles in regulating responses to mitogens and growth factors including insulin, and serves as a master regulator of cellular homeostasis. Because of the extreme radiosensitivity of A-T cells, inhibitors of ATM would be attractive as radiosensitizers for GBM and other types of cancers. Recently, small molecule inhibitors based on the PI3K inhibitor LY294002 were developed by KuDOS Pharmaceuticals, Ltd, that specifically target the ATM kinase. These inhibitors are effective in the nanomolar to micromolar range and radiosensitize various human tumor cell lines in vitro. We recently demonstrated that these inhibitors also suppress DNA double-strand break (DSB) repair. Herein, a second-generation derivative, KU-60019, based on the effective and extensively used predecessor KU-55933, will be tested in vitro and in vivo to determine whether it would be a safe and effective radiosensitizer for GBM. Initial experiments will use brain organotypic slice cultures to characterize the effects of KU-60019 on various radiation responses and whether normal brain with its different types of cells and the tumor cells are affected differently. Specific attention will be given to the possible adverse effects of KU-60019 on neural stem and progenitor cells. Then, the evaluation of KU-60019 as a radiosensitizer of human orthotopic GBM xenografts grown in nude mice will be determined by non-invasive bioluminescence and fluorescence imaging. We expect to determine whether KU-60019 would be a safe and effective radiosensitizer for GBM. We also expect to establish the foundation for an in vivo mouse model system that would allow us to investigate the basic radiobiological properties of neural stem and progenitor cells and assess their behavior and response to KU-60019 therapy.