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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：
Atsuo Sasaki
金额：
$ 41.35万
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/10296056
关键词：
Address Anabolism 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 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 IMPDH2 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 Pharmacology Phosphotransferases Primary Brain Neoplasms Prodrugs 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 Structure System Testing Therapeutic Therapeutic Effect Transfer RNA Up-Regulation Work blood-brain barrier disruption cancer cell cancer clinical trial cell killing clinically relevant design improved in vivo inhibitor/antagonist insight metabolomics mutant mycophenolate mofetil novel novel therapeutic intervention novel therapeutics 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 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

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