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：
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
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

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

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

概括胶质母细胞瘤多形（GBM）是所有脑肿瘤中最具侵略性和致命性的。尽管付出了广泛的努力为了改善治疗，当前的GBM治疗仅略略延长中位生存率从大约12个月延长超过14个月。已经尝试了各种策略来改善治疗，但所有这些策略都被证明是逐渐比当前的护理标准好。没有发现神经胶质瘤的独特特性可以使它们成为治疗的有效靶标，GBM的预后将继续非常差。我们实验室的长期目标是了解GTP代谢在癌症增长中的基本作用 GBM作为模型系统。为此，我们在分子细胞（2016）中发表了脂质激酶的发现 PI5P4Kβ作为一种细胞内GTP传感器，以减轻细胞对GTP的需求。在调查GTP的过程中代谢，我们进一步发表在自然细胞生物学（2019）中，增加了GTP合成直接相关 GBM肿瘤增殖的侵略性。 GTP代谢重编程由肌苷一磷酸脱氢酶2（IMPDH2）的上调，激活从头GTP生物合成核糖体生物发生和蛋白质合成的促进。重要的是，抗治疗的独特特征 GBM干细胞（GSC）是对从头GTP合成的独家依赖性。在未发表的初步中研究，我们发现IMPDH2明显抵抗活性氧的破坏作用物种（ROS）。重要的是，电离辐射通过DNA直接断裂在肿瘤上发挥其细胞杀伤作用其次是ROS的产生，占DNA病变的60-70％。这个高玫瑰电阻似乎是IMPDH2的关键和特定特征。指导该提议的中心假设是 IMPDH2通过i）促进GBM的生长i）具有抗破坏性效应诱导ROS的抗性，II）诱导GSC存活所需的从头GTP合成。我们将通过探索分子来测试这一点使用IMPDH2及其突变体的结构和分子分析的ROS抗性机制。（AIM 1）以及GSC对从头GTP生物合成的高度依赖（AIM 2）。在AIM 3中，我们将使用IMPDH2 抑制剂，霉酚酸（MPA）及其前药，霉酚酸酯（MMF）在体内GBM模型上跟踪肿瘤生长和GBM微环境的次要目标，以确定这些抑制剂是否是否凭借其抗炎和抗血管生成特性，可减少通常看到的脑水肿在GBM中（AIM 3）。这些目标的完成将确定IMPDH2调节DE的机制 Novo GTP合成，从而驱动GBM肿瘤生长。这些见解，将临床前数据合并到 MMF是已批准其免疫抑制作用的药物，有可能导致快速翻译到人类GBM。项目描述

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.