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

本K08提案将完成丹尼尔R博士。Wahl，MD，PhD的长期培训 指导一个独立的研究项目，旨在改善对病人的治疗的职业目标 与胶质母细胞瘤（GBM）之间的相互作用，通过了解异常GBM代谢和 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，在放射领域取得了成功 肿瘤学这项建议建立在瓦尔博士以前获得的辐射生物学和生物学的专业知识的基础上。 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。这些建立和 新获得的技能将被整合，以提高我们对代谢适应的理解， 与放射反应的相互作用，并测试GBM患者的新治疗选择。的 本文中提出的工作将在主要指导人西奥多S的指导下进行。劳伦斯， 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。Burant医学博士，博士和一个顾问团队， 在代谢组学、GBM小鼠模型和 计算生物学以及长期的成功指导记录。这个五年计划包括 正式的课程，专业发展和逐步独立的研究， 确保生产力和成功过渡到独立的里程碑。 几乎所有的胶质母细胞瘤（GBM）复发的高剂量辐射领域。We previously showed 抑制GBM的异常代谢是消除辐射抗性的有效策略。我们 此后，我对23种遗传上不同的GBM细胞系进行了无偏代谢组学分析， 已经暗示嘌呤和嘧啶的从头合成是最相关的代谢途径 GBM的辐射抗性。对于K08奖中提出的工作，我们将使用基于通量的 代谢组学、患者源性GBM异种移植模型和FDA批准的从头抑制剂 核苷酸合成来检验电离辐射直接增加从头合成的活性的假设。 GBM中嘌呤和嘧啶的合成，抑制这些途径将增加放射治疗 通过减弱DNA损伤反应因为构成正常细胞的终末分化细胞 大脑主要依赖于核苷酸补救而不是从头合成， 针对这些通路的获批药物在患者中耐受性良好，我们认为， 核苷酸合成可能是GBM中选择性放射增敏的有希望的治疗靶点。

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.