Therapeutic resistance and aggressive malignancy in glioblastomas: the contribution of GTP metabolism through regulation by IMPDH2

胶质母细胞瘤的治疗耐药性和侵袭性恶性肿瘤:IMPDH2 调节 GTP 代谢的贡献

基本信息

  • 批准号:
    10296056
  • 负责人:
  • 金额:
    $ 41.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-07 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Summary Glioblastoma multiforme (GBM) is the most aggressive and lethal of all brain tumors. Despite extensive efforts to improve treatment, current GBM therapy only marginally prolongs median survival from about 12 months to over 14 months. A variety of strategies have been attempted to improve treatment, but all have proven to be only incrementally better than the current standard of care. Without the discovery of unique properties of gliomas that could make them effective targets for treatment, GBM will continue to have an extremely poor prognosis. The long-term goal of our laboratory is to understand the fundamental role of GTP metabolism in cancer growth using GBM as a model system. To that end, we published in Molecular Cell (2016) the discovery of lipid kinase PI5P4Kβ as an intracellular GTP sensor regulating the cells needs for GTP. In the course of investigating GTP metabolism, we further published in Nature Cell Biology (2019) that increased GTP synthesis is directly linked to the aggressive nature of GBM tumor proliferation. The GTP metabolic reprogramming is induced by upregulation of inosine monophosphate dehydrogenase-2 (IMPDH2), activating de novo GTP biosynthesis for the promotion of ribosomal biogenesis and protein synthesis. Importantly, a unique feature of treatment resistant GBM stem-like cells (GSCs) is exclusive dependence on de novo GTP synthesis. In unpublished preliminary studies, we have discovered that IMPDH2 is markedly resistant to the damaging effects of reactive oxygen species (ROS). Importantly, ionizing radiation exerts its cell killing effect on tumor through DNA breaks directly and secondary to the generation of ROS, which accounts for 60-70 % of DNA lesions. This high ROS resistance appears to a critical and specific feature of IMPDH2. The central hypothesis guiding this proposal is that IMPDH2 promotes GBM growth by i) being resistant to the damaging effect radiation induced ROS, ii) inducing de novo GTP synthesis required for GSCs survival. We will test this by exploring the molecular mechanisms of the ROS resistance using the structural and molecular analyses of IMPDH2 and its mutants. (Aim 1) and GSC’s high dependence on de novo GTP biosynthesis (Aim 2). In Aim 3, we will use the IMPDH2 inhibitor, mycophenolic acid (MPA) and its prodrug, mycophenolate mofetil (MMF) on in vivo GBM models tracking tumor growth and GBM microenvironments with a secondary objective to determine if these inhibitors, by virtue of their anti-inflammatory and anti-angiogenic properties, reduce the cerebral edema commonly seen in GBM (Aim 3). Completion of these aims will identify the mechanisms through which IMPDH2 regulates de novo GTP synthesis thereby driving on GBM tumor growth. These insights, when combined preclinical data on MMF, a drug already approved for its immunosuppressive effects, has the potential to result in rapid translation to human GBM. Project Description
总结

项目成果

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Atsuo Sasaki其他文献

Atsuo Sasaki的其他文献

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{{ truncateString('Atsuo Sasaki', 18)}}的其他基金

Mechanistic role of phosphatidylinositol 5-phosphate 4-kinase beta in GTP-dependent lysosomal acidification for stress-resilient cell growth and metabolism
磷脂酰肌醇5-磷酸4-激酶β在GTP依赖性溶酶体酸化对应激恢复细胞生长和代谢中的机制作用
  • 批准号:
    10592707
  • 财政年份:
    2022
  • 资助金额:
    $ 41.35万
  • 项目类别:
Mechanistic role of phosphatidylinositol 5-phosphate 4-kinase beta in GTP-dependent lysosomal acidification for stress-resilient cell growth and metabolism
磷脂酰肌醇5-磷酸4-激酶β在GTP依赖性溶酶体酸化中对应激恢复细胞生长和代谢的机制作用
  • 批准号:
    10797540
  • 财政年份:
    2022
  • 资助金额:
    $ 41.35万
  • 项目类别:
Therapeutic resistance and aggressive malignancy in glioblastomas: the contribution of GTP metabolism through regulation by IMPDH2
胶质母细胞瘤的治疗耐药性和侵袭性恶性肿瘤:IMPDH2 调节 GTP 代谢的贡献
  • 批准号:
    10682618
  • 财政年份:
    2021
  • 资助金额:
    $ 41.35万
  • 项目类别:
Therapeutic resistance and aggressive malignancy in glioblastomas: the contribution of GTP metabolism through regulation by IMPDH2
胶质母细胞瘤的治疗耐药性和侵袭性恶性肿瘤:IMPDH2 调节 GTP 代谢的贡献
  • 批准号:
    10447195
  • 财政年份:
    2021
  • 资助金额:
    $ 41.35万
  • 项目类别:
Synthetic Lethal Combination of KRP203/Fingolimod with PI3K signaling for glioblastoma multiforme death by catastrophic vacuolization
KRP203/芬戈莫德与 PI3K 信号传导的合成致死组合可导致多形性胶质母细胞瘤灾难性空泡化死亡
  • 批准号:
    9335996
  • 财政年份:
    2016
  • 资助金额:
    $ 41.35万
  • 项目类别:
Synthetic Lethal Combination of KRP203/Fingolimod with PI3K signaling for glioblastoma multiforme death by catastrophic vacuolization
KRP203/芬戈莫德与 PI3K 信号传导的合成致死组合可导致多形性胶质母细胞瘤灾难性空泡化死亡
  • 批准号:
    9227435
  • 财政年份:
    2016
  • 资助金额:
    $ 41.35万
  • 项目类别:
Targeting the Novel PI5P4K Pathway to Induce Glioblastoma Senescence
靶向新的 PI5P4K 途径诱导胶质母细胞瘤衰老
  • 批准号:
    8935962
  • 财政年份:
    2014
  • 资助金额:
    $ 41.35万
  • 项目类别:
Targeting the Novel PI5P4K Pathway to Induce Glioblastoma Senescence
靶向新的 PI5P4K 途径诱导胶质母细胞瘤衰老
  • 批准号:
    8800075
  • 财政年份:
    2014
  • 资助金额:
    $ 41.35万
  • 项目类别:
Chemical probes that modulate a stress pathway phosphatidylinositol 5-phosphate 4
调节应激途径磷脂酰肌醇 5-磷酸 4 的化学探针
  • 批准号:
    8262562
  • 财政年份:
    2012
  • 资助金额:
    $ 41.35万
  • 项目类别:
Chemical Probes That Modulate Phosphatidylinositol-5-Phosphate 4-Kinase Activity
调节磷脂酰肌醇 5 磷酸 4 激酶活性的化学探针
  • 批准号:
    8403186
  • 财政年份:
    2012
  • 资助金额:
    $ 41.35万
  • 项目类别:

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  • 批准号:
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