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

这份K08提案将完成丹尼尔·R·瓦尔博士的医学博士培训，为他的长期 指导旨在改善患者治疗的独立研究计划的职业目标 通过了解胶质母细胞瘤(GBM)代谢异常和血管内皮细胞生长因子的相互作用 辐射反应。Wahl博士是加州大学伯克利分校 密歇根大学放射肿瘤学在放射领域取得了公认的成功 肿瘤学。这项建议建立在Wahl博士之前在辐射生物学和 新陈代谢靶向药物的机制，以发展基于通量的代谢组学研究的专门知识， 大数据集的生物信息学分析和GBM的高级鼠标建模。这些都是既定的和 新获得的技能将被整合起来，以提高我们对代谢适应如何 与辐射反应的相互作用，并测试GBM患者的新治疗选择。这个 这里提出的工作将在主要导师西奥多·S·劳伦斯的指导下进行， 医学博士、博士和共同导师玛丽亚·卡斯特罗博士和查尔斯·A·伯兰特博士和 在新陈代谢组学、小鼠GBM建模和 计算生物学，以及指导成功的长期记录。这个五年计划包括 正规课程、专业发展和逐步独立的研究，并有明确的 确保生产率和向独立的成功过渡的里程碑。 几乎所有的胶质母细胞瘤(GBM)都在高剂量照射野内复发。我们之前展示了 抑制GBM的异常代谢是消除辐射抗性的有效策略。我们 自那以后，他们对23个基因不同的GBM细胞系进行了无偏见的代谢组分析，这些细胞系 已经牵涉到从头开始的嘌呤和嘧啶的合成作为与 GBM的抗辐射性能。对于本K08奖中提出的工作，我们将使用基于熔剂的 代谢组学、患者来源的GBM异种移植模型和FDA批准的新生抑制剂 核苷酸合成来验证电离辐射直接增加从头开始活性的假说 基底膜中嘌呤和嘧啶合成以及抑制这些途径将增强放射治疗 通过削弱DNA损伤反应。因为组成正常的终末分化细胞 大脑主要依赖核苷酸回收，而不是从头合成，因为FDA已经 针对这些通路的已批准药物在患者中耐受性良好，我们相信从头开始 核苷酸合成有望成为GBM选择性放射增敏的治疗靶点。

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.