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，并且是一致致命的 中位生存期约为1.5年。与手术和化疗一样，放射治疗（RT）是一种 对几乎所有GBM患者进行关键治疗，并一再提高患者生存率 在多个随机试验中。尽管如此，80%的GBM在高剂量RT视野内复发。因此 迫切需要开发克服GBM RT抗性的策略，以进一步改善患者的 结果。GBM细胞表现出严重的癌症特异性代谢异常，包括升高的细胞内代谢水平。 嘌呤合成，以促进增殖、侵袭和存活。我们已经发现， 嘌呤合成升高的表型也通过促进 修复RT诱导的DNA损伤。最近，我们已经发现，非恶性细胞在 GBM微环境促进胶质瘤细胞嘌呤代谢和RT抗性。在这 研究建议，我们将（1）确定非恶性细胞的代谢机制， 调节GBM代谢和RT抗性，（2）测量这些代谢产物的活性， 在患者的GBM肿瘤中，（3）通过以下途径中断GBM患者的这种调节： 将FDA批准的和CNS渗透的嘌呤代谢抑制剂与标准的 护理RT和替莫唑胺在1B期临床试验。