Targeting purine biosynthesis to radiosensitize glioblastoma
靶向嘌呤生物合成使胶质母细胞瘤放射增敏
基本信息
- 批准号:10229208
- 负责人:
- 金额:$ 6.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdenineAdenosineAllyAmino AcidsAnabolismBrain NeoplasmsCarbonCell Culture TechniquesCellsChemotherapy and/or radiationClinical TrialsCommunicationDNA DamageDNA-dependent protein kinaseDataEventExhibitsFDA approvedFRAP1 geneFutureGlioblastomaGlucoseGuanineGuanosineHypoxanthinesLeadLeftLinkMalignant NeoplasmsMeasurementMediatingMediator of activation proteinMetabolicMetabolic PathwayMetabolismMethodologyMethodsMichiganModelingMonosaccharidesMusNational Research Service AwardsNatureOperative Surgical ProceduresOrangesPathway interactionsPatient-Focused OutcomesPatientsPharmacologyPrimary Brain NeoplasmsProto-Oncogene Proteins c-aktPublishingPurine AntagonistPurinesRadiationRadiation Dose UnitRadiation Induced DNA DamageRadiation therapyResearchResearch ProposalsResistanceSignal PathwaySignal TransductionSupplementationTechniquesTestingUnited States National Institutes of HealthUniversitiesWorkadenylatebaseexpectationexperimental studygenetic approachguanylateimprovedin vitro Modelin vivoin vivo Modelinhibitor/antagonistmetabolic phenotypemetabolomicsmycophenolate mofetilnovelnucleobasepatient derived xenograft modelpurine metabolismradiation effectradiation resistanceradiation responseradioresistantrandomized trialrepairedresponsestable isotopesugartargeted treatmenttherapy resistanttumor
项目摘要
Project Summary/Abstract
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. Using mice bearing intracranial orthotopic patient-derived brain tumors, my
research has established that the metabolic phenotype of elevated purine synthesis also mediates resistance to
RT in GBM by promoting the repair of RT-induced DNA damage. This purine-mediated RT resistance can be
overcome by treatment with mycophenolate mofetil (MMF), an FDA-approved and CNS-penetrant inhibitor of
purine biosynthesis.
In this research proposal I will determine how the RT response and purine synthesis regulate one another in
GBM. By employing a variety of cutting-edge metabolomic techniques and patient-derived GBM models, I will 1)
define the biosynthetic pathway GBMs use to generate purines, and 2) determine the RT response mechanism
by which GBMs increase purine levels to resist RT-induced DNA damage.
Findings from the experiments proposed here will expand our understanding of how tumors modulate
metabolism to promote therapeutic resistance, inform how to combine metabolic inhibitors with standard
therapies, and lay the mechanistic groundwork for clinical trials at the University of Michigan that targeting purine
biosynthesis to augment RT in GBM patients.
项目概要/摘要
胶质母细胞瘤 (GBM) 是最常见的侵袭性原发性脑肿瘤,均具有致命性,中位死亡率为
生存期约1.5年。与手术和化疗一样,放疗 (RT) 是几乎所有患者的关键治疗方法
每位患有 GBM 的患者都在多项随机试验中多次改善了患者的生存率。尽管如此,80%
GBM 在高剂量放疗野内复发。因此,迫切需要制定克服 GBM 的策略
RT 抵抗可进一步改善患者的治疗效果。
GBM 细胞表现出严重的癌症特异性代谢异常,包括嘌呤合成升高,以促进
增殖、入侵和生存。使用携带颅内原位患者源性脑肿瘤的小鼠,我的
研究已证实嘌呤合成升高的代谢表型也介导耐药性
RT 在 GBM 中通过促进 RT 诱导的 DNA 损伤的修复。这种嘌呤介导的 RT 抗性可以是
通过使用吗替麦考酚酯 (MMF) 治疗可以克服这一问题,MMF 是 FDA 批准的中枢神经系统渗透抑制剂
嘌呤生物合成。
在这项研究计划中,我将确定 RT 反应和嘌呤合成如何在
GBM。通过采用各种尖端代谢组学技术和患者来源的 GBM 模型,我将 1)
定义 GBM 用于生成嘌呤的生物合成途径,2) 确定 RT 反应机制
GBM 通过增加嘌呤水平来抵抗 RT 诱导的 DNA 损伤。
这里提出的实验结果将扩大我们对肿瘤如何调节的理解
代谢以促进治疗耐药性,告知如何将代谢抑制剂与标准药物相结合
疗法,并为密歇根大学针对嘌呤的临床试验奠定机制基础
生物合成以增强 GBM 患者的 RT。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrew Joseph Scott的其他文献
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{{ truncateString('Andrew Joseph Scott', 18)}}的其他基金
Targeting purine biosynthesis to radiosensitize glioblastoma
靶向嘌呤生物合成使胶质母细胞瘤放射增敏
- 批准号:
10376755 - 财政年份:2021
- 资助金额:
$ 6.82万 - 项目类别:
Targeting purine biosynthesis to radiosensitize glioblastoma
靶向嘌呤生物合成使胶质母细胞瘤放射增敏
- 批准号:
10598506 - 财政年份:2021
- 资助金额:
$ 6.82万 - 项目类别:
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