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
• 负责人: Atsuo Sasaki
• 金额: $ 38.77万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10682618
• 关键词: Address; Anabolism; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Automobile Driving; Biochemical; Biogenesis; Biological Models; Biology; Blood Vessels; Brain Neoplasms; Cell Culture Techniques; Cell Survival; Cells; Cellular biology; Cerebral Edema; Clinical Trials; Collaborations; Coupled; Cryoelectron Microscopy; DNA; DNA Repair; DNA Sequence Alteration; DNA lesion; Data; Dependence; Edema; Energy Metabolism; Enzymes; FDA approved; Fostering; Free Radicals; Generations; Genetic; Genetic Transcription; Glioblastoma; Glioma; Goals; Growth; Guanosine Triphosphate; Human; Hypertrophy; IMP Dehydrogenase; IMPDH1 gene; Immunocompetent; Immunosuppression; Inosine Monophosphate; Ionizing radiation; Isoenzymes; Japan; Knowledge; Laboratories; Link; Lipids; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; Mycophenolic Acid; Nature; Nucleotides; Oxidoreductase; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphotransferases; Primary Brain Neoplasms; Prodrugs; Productivity; Prognosis; Proliferating; Property; Protein Biosynthesis; Publishing; Radiation Oncology; Radiation therapy; Reactive Oxygen Species; Regulation; Research; Resistance; Ribosomal RNA; Ribosomes; Roentgen Rays; Role; Secondary to; Signal Transduction; System; Testing; Therapeutic; Therapeutic Effect; Transfer RNA; Up-Regulation; Work; blood-brain barrier disruption; cancer cell; cell killing; clinically relevant; design; improved; in vivo; inhibitor; insight; metabolomics; mutant; mycophenolate mofetil; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; phosphatidylinositol 5-phosphate; pre-clinical; preclinical study; public health relevance; radiation effect; radiation resistance; sensor; standard of care; stem-like cell; therapy resistant; translation to humans; tumor; tumor growth; tumor initiation; tumorigenesis

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 多形性胶质母细胞瘤（GBM）是所有脑肿瘤中最具侵袭性和致命性的。尽管作出了广泛的努力 为了改善治疗，目前的GBM治疗仅略微延长中位生存期约12个月至20个月。 超过14个月已经尝试了各种各样的策略来改善治疗，但所有这些策略都被证明是唯一的。 比目前的护理标准更好。如果没有发现神经胶质瘤的独特特性， 尽管GBM可能成为有效的治疗靶点，但GBM的预后仍将非常差。的 我们实验室的长期目标是了解GTP代谢在癌症生长中的基本作用， GBM作为模型系统。为此，我们在Molecular Cell（2016）上发表了脂质激酶的发现， PI 5 P4 K β作为细胞内GTP传感器调节细胞对GTP的需要。在调查GTP的过程中， 我们进一步在Nature Cell Biology（2019）上发表了一篇文章，指出GTP合成的增加与代谢直接相关。 GBM肿瘤增殖的侵袭性。GTP代谢重编程是由 上调肌苷一磷酸脱氢酶-2（IMPDH 2），激活GTP的从头生物合成， 促进核糖体生物发生和蛋白质合成。重要的是，耐药的一个独特特征是 胶质母细胞样干细胞（GBM stem-like cells，GSC）完全依赖于GTP的从头合成。在未公布的初步 研究中，我们发现IMPDH 2对活性氧的破坏作用具有显著的抵抗力 物种（ROS）。重要的是，电离辐射直接通过DNA断裂发挥其对肿瘤细胞的杀伤作用 其次是ROS的产生，ROS占DNA损伤的60- 70%。如此高的ROS 抗性似乎是IMPDH 2的关键和特异性特征。指导这一建议的核心假设是 IMPDH 2通过i）抵抗辐射诱导的ROS的损伤作用，ii） 诱导GSC存活所需的从头GTP合成。我们将通过探索 使用IMPDH 2及其突变体的结构和分子分析的ROS抗性机制。 (Aim 1）和GSC对从头GTP生物合成的高度依赖性（Aim 2）。在目标3中，我们将使用IMPDH 2 抑制剂霉酚酸（MPA）及其前药霉酚酸酯（MMF）对体内GBM模型影响 跟踪肿瘤生长和GBM微环境，次要目的是确定这些抑制剂， 由于其抗炎和抗血管生成特性，减少常见的脑水肿 GBM（目标3）。这些目标的完成将确定IMPDH第二届会议通过哪些机制来管理这些问题。 新GTP合成，从而驱动GBM肿瘤生长。这些见解，当结合临床前数据 霉酚酸酯是一种已经被批准具有免疫抑制作用的药物， 人类GBM。 项目描述

项目成果

Beyond Warburg: LDHA activates RAC for tumour growth.

• DOI: 10.1038/s42255-022-00709-3
• 发表时间: 2022-12
• 期刊: NATURE METABOLISM
• 影响因子: 20.8
• 作者: Osaka, Natsuski;Sasaki, Atsuo T.
• 通讯作者: Sasaki, Atsuo T.

The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity.

• DOI: 10.1016/j.str.2022.04.004
• 发表时间: 2022-06-02
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Takeuchi, Koh;Ikeda, Yoshiki;Senda, Miki;Harada, Ayaka;Okuwaki, Koji;Fukuzawa, Kaori;Nakagawa, So;Yu, Hong Yang;Nagase, Lisa;Imai, Misaki;Sasaki, Mika;Lo, Yu-Hua;Ito, Doshun;Osaka, Natsuki;Fujii, Yuki;Sasaki, Atsuo T.;Senda, Toshiya
• 通讯作者: Senda, Toshiya

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin

Schlafen11 的表观遗传上调使 WNT 和 SHH 激活的髓母细胞瘤对顺铂敏感

• DOI: 10.1093/neuonc/noac243
• 发表时间: 2022
• 期刊: Neuro-Oncology
• 影响因子: 15.9
• 作者: Nakata Satoshi;Murai Junko;Okada Masayasu,,,,,Tateishi Kensuke;Yamashita Shinji;Eberhart Charles G;Natsumeda Manabu
• 通讯作者: Natsumeda Manabu

Functional molecular evolution of a GTP sensing kinase: PI5P4Kβ.

• DOI: 10.1111/febs.16763
• 发表时间: 2023-09
• 期刊: The FEBS journal