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: 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
• 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

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.

项目概要/摘要 胶质母细胞瘤 (GBM) 是最常见的侵袭性原发性脑肿瘤，均具有致命性，中位死亡率为 生存期约1.5年。与手术和化疗一样，放疗 (RT) 是几乎所有患者的关键治疗方法 每位患有 GBM 的患者都在多项随机试验中多次改善了患者的生存率。尽管如此，80% GBM 在高剂量放疗野内复发。因此，迫切需要制定克服 GBM 的策略 RT 抵抗可进一步改善患者的治疗效果。 GBM 细胞表现出严重的癌症特异性代谢异常，包括嘌呤合成升高，以促进 增殖、入侵和生存。使用携带颅内原位患者源性脑肿瘤的小鼠，我的 研究已证实嘌呤合成升高的代谢表型也介导耐药性 RT 在 GBM 中通过促进 RT 诱导的 DNA 损伤的修复。这种嘌呤介导的 RT 抗性可以是 通过使用吗替麦考酚酯 (MMF) 治疗可以克服这一问题，MMF 是 FDA 批准的中枢神经系统渗透抑制剂 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在 GBM。通过采用各种尖端代谢组学技术和患者来源的 GBM 模型，我将 1) 定义 GBM 用于生成嘌呤的生物合成途径，2) 确定 RT 反应机制 GBM 通过增加嘌呤水平来抵抗 RT 诱导的 DNA 损伤。 这里提出的实验结果将扩大我们对肿瘤如何调节的理解 代谢以促进治疗耐药性，告知如何将代谢抑制剂与标准药物相结合 疗法，并为密歇根大学针对嘌呤的临床试验奠定机制基础 生物合成以增强 GBM 患者的 RT。