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

• 批准号: 10376755
• 负责人: Andrew Joseph Scott
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10376755
• 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; 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

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.

项目总结/摘要 胶质母细胞瘤（GBM）是最常见的侵袭性原发性脑肿瘤，平均死亡率为 生存期约1.5年。与手术和化疗一样，放射治疗（RT）是一种关键的治疗方法， 在多项随机试验中，每名GBM患者的生存率都一再提高。尽管如此， GBM在高剂量RT视野内复发。因此，迫切需要制定克服GBM的战略 RT抵抗进一步改善患者结局。 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 增殖、侵袭和存活。使用携带颅内原位患者源性脑肿瘤的小鼠， 研究已经确定，嘌呤合成升高的代谢表型也介导了对 RT通过促进RT诱导的DNA损伤的修复在GBM中发挥作用。这种嘌呤介导的RT抗性可以是 通过霉酚酸酯（MMF）治疗克服，霉酚酸酯是FDA批准的CNS渗透抑制剂， 嘌呤生物合成 在这项研究计划中，我将确定RT反应和嘌呤合成如何相互调节， GBM。通过采用各种尖端代谢组学技术和患者源性GBM模型，我将1） 确定GBM用于产生嘌呤的生物合成途径，以及2）确定RT反应机制 GBM通过其增加嘌呤水平以抵抗RT诱导的DNA损伤。 本文提出的实验结果将扩大我们对肿瘤如何调节 代谢，以促进治疗耐药性，告知如何将联合收割机代谢抑制剂与标准 治疗，并为密歇根大学的临床试验奠定了机制基础， 生物合成以增加GBM患者的RT。