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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