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

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)是一种毁灭性的脑癌,平均生存期仅为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症(Ataxia telangiectasia,A-T)突变体(Ataxia telangiectasia,ATM)是一种重要的基因组监视蛋白,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生长因子(包括胰岛素)的反应中发挥额外的作用,并且充当细胞稳态的主调节剂。由于A-T细胞的极端放射敏感性,ATM的抑制剂作为GBM和其他类型癌症的放射增敏剂将是有吸引力的。最近,KuDOS Pharmaceuticals,Ltd开发了基于PI 3 K抑制剂LY 294002的小分子抑制剂,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。本文中,基于有效且广泛使用的前体KU-55933的第二代衍生物KU-60019将进行体外和体内测试,以确定其是否是GBM的安全有效的放射增敏剂。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的可能不良影响。然后,将通过非侵入性生物发光和荧光成像来确定KU-60019作为在裸鼠中生长的人原位GBM异种移植物的放射增敏剂的评价。我们希望确定KU-60019是否是GBM的安全有效的放射增敏剂。我们还希望建立体内小鼠模型系统的基础,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,平均生存期仅为12个月,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方法。该建议将确定靶向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GBM的安全有效的放射增敏剂。

项目成果

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KRISTOFFER Carl VALERIE其他文献

KRISTOFFER Carl VALERIE的其他文献

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{{ truncateString('KRISTOFFER Carl VALERIE', 18)}}的其他基金

Glioblastoma radioimmunotherapy
胶质母细胞瘤放射免疫治疗
  • 批准号:
    10057915
  • 财政年份:
    2020
  • 资助金额:
    $ 32.31万
  • 项目类别:
Glioblastoma radioimmunotherapy
胶质母细胞瘤放射免疫治疗
  • 批准号:
    10231261
  • 财政年份:
    2020
  • 资助金额:
    $ 32.31万
  • 项目类别:
Novel, orally available ATM inhibitor for glioma conformal radiosensitization
用于神经胶质瘤适形放射增敏的新型口服 ATM 抑制剂
  • 批准号:
    9184543
  • 财政年份:
    2015
  • 资助金额:
    $ 32.31万
  • 项目类别:
Targeting invasion and DNA DSB repair in glioma with a multi-pronged approach.
多管齐下,针对神经胶质瘤的侵袭和 DNA DSB 修复。
  • 批准号:
    8206662
  • 财政年份:
    2010
  • 资助金额:
    $ 32.31万
  • 项目类别:
Targeting invasion and DNA DSB repair in glioma with a multi-pronged approach.
多管齐下,针对神经胶质瘤的侵袭和 DNA DSB 修复。
  • 批准号:
    8059203
  • 财政年份:
    2010
  • 资助金额:
    $ 32.31万
  • 项目类别:
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:
    8327481
  • 财政年份:
    2009
  • 资助金额:
    $ 32.31万
  • 项目类别:
Radiation-induced ATM and ERK signaling in DSB repair
DSB 修复中辐射诱导的 ATM 和 ERK 信号传导
  • 批准号:
    7448331
  • 财政年份:
    2009
  • 资助金额:
    $ 32.31万
  • 项目类别:
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
  • 财政年份:
    2009
  • 资助金额:
    $ 32.31万
  • 项目类别:
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:
    8517834
  • 财政年份:
    2009
  • 资助金额:
    $ 32.31万
  • 项目类别:
Radiation-induced ATM and ERK signaling in DSB repair
DSB 修复中辐射诱导的 ATM 和 ERK 信号传导
  • 批准号:
    8073827
  • 财政年份:
    2009
  • 资助金额:
    $ 32.31万
  • 项目类别:

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