ATM as target for malignant glioma radiosensitization.

描述(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，几乎没有治疗选择。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)是一种重要的基因组监测蛋白，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。据认为，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发挥额外的作用，并作为细胞内稳态的主要调节因子。由于A-T细胞对辐射的极端敏感性，ATM抑制剂作为GBM和其他类型癌症的放射增敏剂具有很大的吸引力。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。在此，基于有效和广泛使用的前身KU-60019的第二代衍生物KU-55933将进行体外和体内试验，以确定它是否为一种安全有效的基底膜放射增敏剂。最初的实验将使用大脑器官型切片培养来表征KU-60019对各种辐射反应的影响，以及不同类型细胞和肿瘤细胞的正常大脑是否受到不同的影响。将特别注意KU-60019对神经干细胞和祖细胞可能产生的不良影响。然后，将通过非侵入性生物发光和荧光成像来确定KU-60019作为人骨髓基质裸鼠原位移植的放射增敏剂的评价。我们希望确定KU-60019是否是一种安全有效的基底膜放射增敏剂。我们还希望为建立体内小鼠模型系统奠定基础，该系统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，并评估它们的行为和对KU-60019治疗的反应。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，几乎没有治疗选择。GBM的标准治疗方法是手术后再进行放射治疗或放化疗。因此，迫切需要更有效的治疗方法。这项提议将确定一种针对共济失调毛细血管扩张突变(ATM)激酶的高度特异的小分子抑制剂是否会是一种安全有效的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.