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：
8517834
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 33.32万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517834
关键词：
Adverse effects Affect Animals Apoptosis Ataxia Telangiectasia Attention Behavior Biological Availability Biological Models 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 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 bioluminescence imaging cancer cell cancer type caspase-3 cell motility cell type chemoradiation 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

项目摘要

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.

胶质母细胞瘤多形（GBM）是毁灭性的脑癌，平均存活仅为12个月，很少治疗选择。因此，迫切需要更有效的治疗。催化性共济失调（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，包括细胞循环检查点，DNA修复和凋亡。据信，ATM还在调节中扮演其他角色对促分裂剂和生长因子在内的反应，包括胰岛素，并作为细胞的主要调节剂稳态。由于A-T细胞具有极高的放射敏感性，因此ATM的抑制剂将很有吸引力 GBM和其他类型的癌症的放射敏剂。最近，基于PI3K的小分子抑制剂抑制剂LY294002是由专门针对ATM激酶的Kudos Pharmaceuticals，Ltd开发的。这些抑制剂在纳摩尔到微摩尔范围内有效，并将各种人类肿瘤敏感体外细胞系。我们最近证明，这些抑制剂也抑制了DNA双链断裂（DSB）维修。以下是第二代衍生物KU-60019，基于有效和广泛使用的前身KU-55933将在体外和体内进行测试，以确定它是否安全有效 GBM的放射敏剂。最初的实验将使用脑器官切片培养物来表征效果 KU-60019在各种辐射反应上以及与其不同类型的细胞的正常大脑以及肿瘤细胞的影响不同。特别关注KU-60019的可能不良影响在神经茎和祖细胞上。然后，评估KU-60019作为人类的放射敏感器在裸鼠中生长的原位GBM异种移植物将由非侵入性生物发光确定荧光成像。我们希望确定KU-60019是否是安全有效的 GBM的放射敏剂。我们还希望为体内鼠标模型系统建立基础将使我们能够研究神经茎和祖细胞的基本放射生物学特性以及评估其行为和对KU-60019治疗的反应。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug.

DOI：
10.1039/c5ra07987j
发表时间：
2015
期刊：
RSC advances
影响因子：
3.9
作者：
Zolotarskaya OY;Xu L;Valerie K;Yang H
通讯作者：
Yang H

MRE11 and ATM AKTivate pro-survival signaling.

MRE11 和 ATM AKTivate 促生存信号传导。

DOI：
10.4161/cc.10.19.17048
发表时间：
2011
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Golding,SarahE;Valerie,Kristoffer
通讯作者：
Valerie,Kristoffer

Subcutaneous administration of D-luciferin is an effective alternative to intraperitoneal injection in bioluminescence imaging of xenograft tumors in nude mice.

在裸鼠异种移植肿瘤的生物发光成像中，皮下注射 D-荧光素是腹腔注射的有效替代方法。

DOI：
10.1155/2013/689279
发表时间：
2013
期刊：
ISRN Molecular Imaging
影响因子：
0
作者：
Khalil,AshrafA;Jameson,MarkJ;Broaddus,WilliamC;Chung,TheodoreD;Golding,SarahE;Dever,SethM;Rosenberg,Elisabeth;Valerie,Kristoffer
通讯作者：
Valerie,Kristoffer

ATM phosphorylates PP2A subunit A resulting in nuclear export and spatiotemporal regulation of the DNA damage response.