Project 2: Overcoming GBM RT-resistance

项目 2：克服 GBM RT 抵抗

• 批准号: 10554473
• 负责人: Daniel R Wahl
• 金额: $ 25.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554473
• 关键词: Astrocytes; Biological Assay; Brain; Brain Neoplasms; Cells; Clinical Trials; Consumption; DNA Repair; Data; Defect; Dose; Environment; Enzymes; Excision; Exhibits; FDA approved; Genomic approach; Genotype; Glioblastoma; Glioma; Glutamine; Goals; Guanosine Triphosphate; Human; Immunohistochemistry; Implant; Interruption; Invaded; Locally Advanced Malignant Neoplasm; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modeling; Molecular Target; Mus; Neurons; Neurosphere; Neurotransmitters; Newly Diagnosed; Non-Malignant; Nonhomologous DNA End Joining; Operative Surgical Procedures; Organoids; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phase Ib Clinical Trial; Physiological; Primary Brain Neoplasms; Proliferating; Purine Antagonist; Purines; Radiation; Radiation Dose Unit; Radiation Induced DNA Damage; Radiation Tolerance; Radiosensitization; Recommendation; Recurrence; Regulation; Research; Research Proposals; Resected; Resistance; Role; Serine; Signal Transduction; Testing; Therapeutic; Therapeutic Index; Tumor Tissue; Xenograft Model; cancer cell; chemoradiation; chemotherapy; improved; improved outcome; in vivo; inhibitor; metabolic phenotype; mycophenolate mofetil; patient derived xenograft model; pharmacologic; purine metabolism; radiation resistance; radioresistant; randomized trial; repaired; single-cell RNA sequencing; stable isotope; standard of care; temozolomide; tumor

PROJECT SUMMARY/ABSTRACT (Project 2) 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. We have found that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. Recently, we have discovered that non-malignant cells in the GBM microenvironment promote purine metabolism and RT resistance in glioma cells. In this research proposal, we will (1) determine the metabolic mechanisms by which non-malignant cells regulate GBM metabolism and RT resistance, (2) measure the activity of these metabolic pathways in GBM tumors in patients and (3) interrupt this regulation in patients with GBM by combining an FDA-approved and CNS-penetrant inhibitor of purine metabolism with standard of care RT and temozolomide in a phase 1B clinical trial.

项目概要/摘要（项目 2） 胶质母细胞瘤 (GBM) 是最常见的侵袭性原发性脑肿瘤，并且都是致命的 中位生存期约为 1.5 年。与手术和化疗一样，放疗 (RT) 是一种 几乎所有 GBM 患者都得到了关键治疗，并多次提高了患者的生存率 在多项随机试验中。尽管如此，80% 的 GBM 在高剂量放疗野内会复发。因此，有 迫切需要制定克服 GBM 放疗耐药性的策略，以进一步改善患者的预后 结果。 GBM 细胞表现出严重的癌症特异性代谢异常，包括升高 嘌呤合成，促进增殖、入侵和生存。我们发现代谢 嘌呤合成升高的表型还通过促进 GBM 介导 RT 抵抗 修复 RT 诱导的 DNA 损伤。最近，我们发现，非恶性细胞 GBM微环境促进胶质瘤细胞的嘌呤代谢和RT抵抗。在这个 研究提案中，我们将（1）确定非恶性细胞的代谢机制 调节GBM代谢和RT抵抗，（2）测量这些代谢的活性 (3) 通过以下方式中断 GBM 患者的这种调节： 将 FDA 批准的中枢神经系统渗透性嘌呤代谢抑制剂与标准相结合 1B 期临床试验中的护理 RT 和替莫唑胺。