ATM as target for malignant glioma radiosensitization.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种毁灭性的脑癌，平均生存期只有12个月，治疗选择很少。因此，迫切需要更有效的治疗方法。共济失调毛细血管扩张（Ataxia telangi扩张）突变（ATM）是一种关键的基因组监视蛋白，它调节许多DNA损伤反应，包括细胞周期检查点、DNA修复和细胞凋亡。据信，ATM还在调节对有丝分裂原和包括胰岛素在内的生长因子的反应中起着额外的作用，并作为细胞稳态的主要调节剂。由于A-T细胞的极端放射敏感性，ATM抑制剂将有吸引力作为GBM和其他类型癌症的放射增敏剂。最近，KuDOS制药有限公司开发了基于PI3K抑制剂LY294002的小分子抑制剂，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，并在体外对各种人类肿瘤细胞系具有放射增敏作用。我们最近证明这些抑制剂也抑制DNA双链断裂（DSB）修复。本文将在有效且广泛使用的前代药物KU-55933的基础上，进行第二代衍生药物KU-60019的体外和体内试验，以确定其是否是安全有效的GBM放射增敏剂。初步实验将使用脑器官型切片培养来表征KU-60019对各种辐射反应的影响，以及不同类型细胞的正常大脑和肿瘤细胞是否受到不同的影响。我们将特别关注KU-60019对神经干细胞和祖细胞可能产生的不良影响。然后，通过无创生物发光和荧光成像来评价KU-60019作为裸鼠原位GBM异种移植物的放射增敏剂。我们期望确定KU-60019是否是一种安全有效的GBM放射增敏剂。我们还希望为体内小鼠模型系统建立基础，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，并评估它们对KU-60019治疗的行为和反应。公共卫生相关性：多形性胶质母细胞瘤（GBM）是一种毁灭性的癌症，平均生存期只有12个月，治疗选择很少。GBM的标准治疗是手术后放疗或放化疗。因此，迫切需要更有效的治疗方法。本研究将确定一种靶向ataxia毛细血管扩张突变（ATM）激酶的高特异性小分子抑制剂是否会成为一种安全有效的GBM放射增敏剂。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM) is a devastating cancer with a mean survival of only 12 months and few therapeutic options. Standard treatment of GBM is surgery followed by radiotherapy or chemoradiation. Thus, more effective treatment is urgently needed. This proposal will determine whether a highly specific small molecule inhibitor that targets the ataxia telangiectasia mutated (ATM) kinase would be a safe and efficient radiosensitizer of GBM.