ATM as target for malignant glioma radiosensitization.

ATM 作为恶性胶质瘤放射增敏的靶标。

基本信息

批准号：
7748582
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 32.31万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
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/7748582
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 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 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 public health relevance radiation effect recombinational repair relating to nervous system research study response small hairpin RNA small molecule standard care stem temozolomide tumor tumor growth

项目摘要

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.

描述（由申请人提供）：多形性胶质母细胞瘤 (GBM) 是一种毁灭性脑癌，平均生存期仅为 12 个月，且治疗选择很少。因此，迫切需要更有效的治疗。共济失调毛细血管扩张 (A-T) 突变 (ATM) 是一种关键的基因组监视蛋白，可调节许多 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 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方面也发挥着额外的作用，并作为细胞稳态的主要调节剂。由于 A-T 细胞具有极高的放射敏感性，ATM 抑制剂作为 GBM 和其他类型癌症的放射增敏剂将很有吸引力。最近，KuDOS Pharmaceuticals, Ltd 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至微摩尔范围内有效，并在体外对各种人类肿瘤细胞系放射敏感。我们最近证明这些抑制剂还能抑制 DNA 双链断裂 (DSB) 修复。在此，第二代衍生物 KU-60019 基于有效且广泛使用的前身 KU-55933，将进行体外和体内测试，以确定它是否是 GBM 的安全有效的放射增敏剂。初步实验将使用脑器官切片培养物来表征 KU-60019 对各种辐射反应的影响，以及具有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。将特别关注 KU-60019 对神经干细胞和祖细胞可能产生的不利影响。然后，将通过非侵入性生物发光和荧光成像来评估KU-60019作为在裸鼠中生长的人原位GBM异种移植物的放射增敏剂的评估。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奠定基础，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，并评估它们的行为和对 KU-60019 治疗的反应。公共健康相关性：多形性胶质母细胞瘤 (GBM) 是一种毁灭性癌症，平均生存期仅为 12 个月，且治疗选择很少。 GBM 的标准治疗是手术后进行放疗或放化疗。因此，迫切需要更有效的治疗。该提案将确定针对共济失调毛细血管扩张突变 (ATM) 激酶的高度特异性小分子抑制剂是否是一种安全有效的 GBM 放射增敏剂。