ATM as target for malignant glioma radiosensitization.

ATM 作为恶性胶质瘤放射增敏的靶标。

• 批准号: 8308640
• 负责人: KRISTOFFER Carl VALERIE
• 金额: $ 32.05万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308640
• 关键词: Adverse effects; Affect; Animals; Apoptosis; Ataxia Telangiectasia; Attention; Behavior; Biological Availability; Biological Models; Bioluminescence; Blood - brain barrier anatomy; Brain; Brain Glioblastoma; Brain Injuries; Brain Neoplasms; Cannulas; Cell Culture Techniques; Cell Cycle Checkpoint; Cells; Cerebral hemisphere; Clinical; Convection; Cranial Irradiation; DNA Damage; DNA Double Strand Break; DNA Repair; Devices; Dominant-Negative Mutation; Dose; Double Strand Break Repair; Doxycycline; DsRed; Evaluation; Family; Firefly Luciferases; Foundations; Generations; Genome; Glioblastoma; Glioma; Growth; Growth Factor; Hematoxylin and Eosin Staining Method; Hereditary Disease; Homeostasis; Hormones; Human; Hypoxia; Image; Immune; Immunohistochemistry; In Vitro; Inflammatory; Infusion procedures; Inhibitory Concentration 50; Insulin; Intention; Ionizing radiation; Knock-in Mouse; Life; Link; Luciferases; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Maximum Tolerated Dose; Mitogens; Monitor; Mus; Mutate; NBS1 gene; Neuraxis; Neurologic; Nonhomologous DNA End Joining; Nude Mice; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phosphatidylinositols; Phosphotransferases; Play; Property; Protein Kinase; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Pump; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Role; Signal Pathway; Signal Transduction; Slice; Specificity; Staining method; Stains; Stem cells; Stress; Subfamily lentivirinae; System; Therapeutic; Therapeutic Agents; Therapeutic Index; Therapeutic Intervention; Toxic effect; Transgenic Organisms; Tumor Cell Line; Validation; Veins; Xenograft procedure; ataxia telangiectasia mutated protein; base; cancer cell; cancer type; caspase-3; cell motility; cell type; clinical practice; early onset; effective therapy; fluorescence imaging; homologous recombination; implantation; improved; in vitro testing; in vivo; inhibitor/antagonist; kinase inhibitor; member; migration; mouse model; neoplastic cell; nerve stem cell; nestin protein; preclinical study; pressure; radiation effect; recombinational repair; relating to nervous system; research study; response; small hairpin RNA; small molecule; standard care; stem; temozolomide; tumor; tumor growth

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.

多形性胶质母细胞瘤（GBM）是一种毁灭性的脑癌，平均生存期仅为12个月， 治疗选择因此，迫切需要更有效的治疗。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视蛋白，调节许多DNA损伤反应，包括细胞 循环检查点、DNA修复和细胞凋亡。据信，ATM还在调节 对有丝分裂原和生长因子（包括胰岛素）的反应，并作为细胞增殖的主要调节因子。 体内平衡。由于A-T细胞的极端辐射敏感性，ATM的抑制剂将是有吸引力的，因为它可以抑制A-T细胞。 GBM和其他类型癌症的放射增敏剂。最近，基于PI 3 K的小分子抑制剂 抑制剂LY 294002由KuDOS Pharmaceuticals，Ltd开发，其特异性靶向ATM激酶。 这些抑制剂在纳摩尔至微摩尔范围内是有效的，并且对各种人类肿瘤具有放射增敏作用。 体外细胞系。我们最近证明，这些抑制剂也抑制DNA双链断裂 (DSB)修复.在此，第二代衍生物，KU-60019，基于有效和广泛使用的 前代KU-55933将在体外和体内进行测试，以确定其是否安全有效。 放射增敏剂。最初的实验将使用脑器官型切片培养物来表征效果 KU-60019对各种辐射反应的影响，以及正常大脑是否具有其不同类型的细胞和 肿瘤细胞受到不同的影响。将特别关注KU-60019可能的不良反应 对神经干细胞和祖细胞的影响。然后，对KU-60019作为人放射增敏剂的评价 通过非侵入性生物发光测定在裸鼠中生长的原位GBM异种移植物， 荧光成像我们希望确定KU-60019是否是一种安全有效的 放射增敏剂。我们还期望建立体内小鼠模型系统的基础， 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， 评估他们的行为和对KU-60019治疗的反应。