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

概括 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。尽管付出了巨大的努力 为了改善治疗，目前的 GBM 治疗仅将中位生存期从约 12 个月略微延长至 超过14个月。人们尝试了多种策略来改善治疗，但所有这些都被证明只是无效的 逐渐优于当前的护理标准。如果没有发现神经胶质瘤的独特特性， 虽然 GBM 的预后仍然极差。这 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《分子细胞》(2016) 上发表了脂质激酶的发现 PI5P4Kβ 作为细胞内 GTP 传感器调节细胞对 GTP 的需求。在调查GTP的过程中 代谢，我们进一步发表在 Nature Cell Biology (2019) 上，GTP 合成的增加与 GBM 肿瘤增殖的侵袭性。 GTP 代谢重编程是由以下因素诱导的 上调肌苷单磷酸脱氢酶 2 (IMPDH2)，激活 GTP 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，治疗抵抗的独特特征 GBM 干细胞样细胞 (GSC) 完全依赖于 GTP 从头合成。在未发表的初步 研究发现，IMPDH2 能够显着抵抗活性氧的破坏作用 物种（ROS）。重要的是，电离辐射通过直接破坏DNA对肿瘤发挥细胞杀伤作用 继发于 ROS 的产生，占 DNA 损伤的 60-70%。这么高的活性氧 耐药性似乎是 IMPDH2 的一个关键且特定的特征。指导该提案的中心假设是 IMPDH2 通过 i) 抵抗辐射诱导的 ROS 的破坏作用，ii) 促进 GBM 生长 诱导 GSC 生存所需的从头合成 GTP。我们将通过探索分子机制来测试这一点 使用 IMPDH2 及其突变体的结构和分子分析研究 ROS 抵抗机制。 （目标 1）和 GSC 对从头 GTP 生物合成的高度依赖（目标 2）。在目标 3 中，我们将使用 IMPDH2 体内 GBM 模型中的抑制剂麦考酚酸 (MPA) 及其前药吗替麦考酚酯 (MMF) 跟踪肿瘤生长和 GBM 微环境，次要目标是确定这些抑制剂是否 凭借其抗炎和抗血管生成特性，减轻常见的脑水肿 GBM（目标 3）。完成这些目标将确定 IMPDH2 调节 de 的机制。 新的 GTP 合成从而驱动 GBM 肿瘤生长。这些见解结合了临床前数据 MMF 是一种因其免疫抑制作用而被批准的药物，有可能实现快速转化 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