De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in Glioblastoma

从头核苷酸合成作为放射抗性的介质和胶质母细胞瘤的治疗靶点

• 批准号: 9976480
• 负责人: Daniel R Wahl
• 金额: $ 25.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976480
• 关键词: ATM activation; Adult; Advisory Committees; Award; Bioinformatics; Biological Assay; Bioluminescence; Blood; Brain; Cell Differentiation process; Cell Line; Clinic; Combined Modality Therapy; Computational Biology; DNA Damage; DNA Repair; Development; Development Plans; Doctor of Philosophy; Drug Targeting; Ensure; FDA approved; FRAP1 gene; Foundations; Gamma-H2AX; Glioblastoma; Glutamine; Goals; Growth; Hour; In Vitro; Intracranial Neoplasms; Investigation; Ionizing radiation; K-Series Research Career Programs; Learning; MAP Kinase Gene; Mass Spectrum Analysis; Measures; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Michigan; Modeling; Monitor; Nucleotides; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phenotype; Primary Brain Neoplasms; Productivity; Purines; Pyrimidine; Pyrimidines; Radiation; Radiation Dose Unit; Radiation Genetics; Radiation Oncology; Radiation Tolerance; Radiation therapy; Radiobiology; Radiosensitization; Research; Research Personnel; Ribavirin; Techniques; Testing; Therapeutic Effect; Tracer; Training; Universities; Work; Xenograft Model; Xenograft procedure; base; career; career development; design; ds-DNA; experimental study; improved; in vitro Model; in vivo; inhibitor/antagonist; large datasets; metabolomics; mouse model; novel therapeutics; nucleotide metabolism; pre-clinical; professor; programs; radiation resistance; radiation response; radioresistant; response; skills; success; therapeutic target; tumor growth

This K08 proposal will complete Dr. Daniel R. Wahl, MD, PhD’s training towards his long-term career goal of directing an independent research program that aims to improve treatments for patients with glioblastoma (GBM) by understanding interactions between abnormal GBM metabolism and the radiation response. Dr. Wahl is an Assistant Professor of Radiation Oncology in the Department of Radiation Oncology at the University of Michigan with established success in the field of radiation oncology. This proposal builds on Dr. Wahl’s previously acquired expertise in radiation biology and the mechanisms of metabolically-targeted drugs to develop expertise in flux-based metabolomics studies, bioinformatics analyses of large data sets and advanced mouse modeling of GBM. These established and newly-acquired skills will be integrated to improve our understanding of how metabolic adaptation interactions with the radiation response and to test new therapeutic options for patients with GBM. The work proposed herein will be conducted under the guidance of primary mentor Theodore S. Lawrence, MD, PhD and co-mentors Maria Castro PhD and Charles A. Burant MD, PhD and an advisory team of accomplished investigators with expertise in the fields of metabolomics, mouse modeling of GBM and computational biology as well as a long track record of mentroring success. This 5-year plan includes formal coursework, professional development and progressively independent research, with defined milestones to ensure productivity and a successful transition to independence. Nearly all glioblastoma (GBM) recur within the high dose radiation field. We previously showed that inhibiting abnormal metabolism in GBM is an effective strategy to abrogate radiation-resistance. We have since performed an unbiased metabolomic analysis of 23 genetically distinct GBM cell lines, which has implicated de novo purine and pyrimidine synthesis as the metabolic pathways most associated with radiation resistance in GBM. For the work proposed in this K08 Award, we will use flux-based metabolomics, patient-derived xenograft models of GBM and FDA-approved inhibitors of de novo nucleotide synthesis to test the hypothesis that ionizing radiation directly increases the activity of de novo purine and pyrimidine synthesis in GBM and that inhibition of these pathways will augment radiotherapy by blunting the DNA damage response. Because the terminally-differentiated cells that comprise normal brain predominantly rely on nucleotide salvage rather than de novo synthesis and because already FDA approved drugs targeting these pathways are well-tolerated in patients, we believe that de novo nucleotide synthesis may be a promising therapeutic target for selective radiosensitization in GBM.

该 K08 提案将完成 Daniel R. Wahl 博士（医学博士、哲学博士）的长期培训 指导旨在改善患者治疗的独立研究计划的职业目标 通过了解异常 GBM 代谢与胶质母细胞瘤 (GBM) 之间的相互作用 辐射反应。 Wahl 博士是放射肿瘤学系的助理教授 密歇根大学放射肿瘤学在放射领域取得了既定的成功 肿瘤学。该提案建立在 Wahl 博士之前获得的放射生物学专业知识和 代谢靶向药物的机制，以开发基于通量的代谢组学研究的专业知识， 大数据集的生物信息学分析和 GBM 的高级小鼠建模。这些既定和 新获得的技能将被整合起来，以提高我们对代谢适应如何进行的理解 与放射反应的相互作用并测试 GBM 患者的新治疗方案。这 本文提出的工作将在主要导师 Theodore S. Lawrence 的指导下进行， 医学博士、博士和共同导师玛丽亚·卡斯特罗 (Maria Castro) 博士和查尔斯·A·布兰特 (Charles A. Burant) 医学博士、博士以及顾问团队 在代谢组学、GBM 小鼠建模和 计算生物学以及长期成功的指导记录。这个5年计划包括 正式的课程作业、专业发展和逐步独立的研究，并有明确的规定 确保生产力和成功过渡到独立的里程碑。 几乎所有胶质母细胞瘤 (GBM) 都会在高剂量辐射场内复发。我们之前展示过 认为抑制GBM异常代谢是消除放射抗性的有效策略。我们 此后对 23 种遗传上不同的 GBM 细胞系进行了公正的代谢组学分析， 表明嘌呤和嘧啶的从头合成是与代谢最相关的途径 GBM 的辐射抗性。对于本次 K08 奖中提出的工作，我们将使用基于助焊剂的 代谢组学、患者来源的 GBM 异种移植模型和 FDA 批准的 de novo 抑制剂 核苷酸合成来检验电离辐射直接增加从头活性的假设 GBM 中嘌呤和嘧啶的合成，抑制这些途径将增强放射治疗 通过减弱 DNA 损伤反应。因为构成正常细胞的终末分化细胞 大脑主要依靠核苷酸回收而不是从头合成，因为 FDA 已经 针对这些途径的批准药物在患者中具有良好的耐受性，我们相信从头开始 核苷酸合成可能是 GBM 选择性放射增敏的有前途的治疗靶点。