Targeting purine biosynthesis to radiosensitize glioblastoma

靶向嘌呤生物合成使胶质母细胞瘤放射增敏

基本信息

批准号：
10229208
负责人：
Andrew Joseph Scott
金额：
$ 6.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2021-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229208
关键词：
Acute Adenine Adenosine Ally Amino Acids Anabolism Brain Neoplasms Carbon Cell Culture Techniques Cells Chemotherapy and/or radiation Clinical Trials Communication DNA Damage DNA-dependent protein kinase Data Event Exhibits FDA approved FRAP1 gene Future Glioblastoma Glucose Guanine Guanosine Hypoxanthines Lead Left Link Malignant Neoplasms Measurement Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Methodology Methods Michigan Modeling Monosaccharides Mus National Research Service Awards Nature Operative Surgical Procedures Oranges Pathway interactions Patient-Focused Outcomes Patients Pharmacology Primary Brain Neoplasms Proto-Oncogene Proteins c-akt Publishing Purine Antagonist Purines Radiation Radiation Dose Unit Radiation Induced DNA Damage Radiation therapy Research Research Proposals Resistance Signal Pathway Signal Transduction Supplementation Techniques Testing United States National Institutes of Health Universities Work adenylate base expectation experimental study genetic approach guanylate improved in vitro Model in vivo in vivo Model inhibitor/antagonist metabolic phenotype metabolomics mycophenolate mofetil novel nucleobase patient derived xenograft model purine metabolism radiation effect radiation resistance radiation response radioresistant randomized trial repaired response stable isotope sugar targeted treatment therapy resistant tumor

项目摘要

Project Summary/Abstract Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy, radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT resistance to further improve patient outcomes. GBM cells exhibit profound cancer-specific metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion and survival. Using mice bearing intracranial orthotopic patient-derived brain tumors, my research has established that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. This purine-mediated RT resistance can be overcome by treatment with mycophenolate mofetil (MMF), an FDA-approved and CNS-penetrant inhibitor of purine biosynthesis. In this research proposal I will determine how the RT response and purine synthesis regulate one another in GBM. By employing a variety of cutting-edge metabolomic techniques and patient-derived GBM models, I will 1) define the biosynthetic pathway GBMs use to generate purines, and 2) determine the RT response mechanism by which GBMs increase purine levels to resist RT-induced DNA damage. Findings from the experiments proposed here will expand our understanding of how tumors modulate metabolism to promote therapeutic resistance, inform how to combine metabolic inhibitors with standard therapies, and lay the mechanistic groundwork for clinical trials at the University of Michigan that targeting purine biosynthesis to augment RT in GBM patients.

项目摘要/摘要胶质母细胞瘤（GBM）是最常见的侵袭性原发性脑肿瘤，中位数均匀致命大约1。5年的生存。像手术和化学疗法一样，放射线（RT）几乎是关键的治疗方法每个患有GBM的患者，并在多个随机试验中反复改善了患者的生存。仍然，有80％ GBMS在高剂量RT场内复发。因此，迫切需要制定克服GBM的策略 RT抵抗力以进一步改善患者预后。 GBM细胞表现出深刻的癌症特异性代谢异常，包括嘌呤合成升高，以燃料扩散，入侵和生存。使用含有颅内原位患者衍生的脑肿瘤的小鼠，我研究表明，嘌呤合成升高的代谢表型也介导了对通过促进RT诱导的DNA损伤修复GBM的RT。这种嘌呤介导的RT电阻可以是通过用霉酚酸酯（MMF）治疗，一种经FDA批准的和CNS penertrant抑制剂的治疗嘌呤生物合成。在这项研究建议中，我将确定RT响应和嘌呤合成如何相互调节 GBM。通过采用各种尖端的代谢组技术和患者衍生的GBM型号，我将1）定义生物合成途径GBM用于生成嘌呤的使用，2）确定RT响应机制 GBM提高嘌呤水平以抵抗RT诱导的DNA损伤。此处提出的实验的发现将扩大我们对肿瘤如何调节的理解代谢以促进治疗性抗性，告知如何将代谢抑制剂与标准结合起来疗法，并在密歇根大学为临床试验奠定了机械基础。 GBM患者增强RT的生物合成。