Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors

用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证

基本信息

项目摘要

Project Summary/Abstract Primary and metastatic central nervous system tumors (CNS) are associated with a high degree of morbidity and mortality. There is a need for new and more effective strategies for diagnosing, treating and monitoring patients with primary and metastatic CNS tumors. Methodologies that address the need for molecular information that is required for the use of precision medicine and targeted therapies, in patients with CNS tumors, are limited. A liquid biopsy assay will facilitate early molecular characterization and monitoring of patients with CNS tumors and will revolutionize patient management. Studies have shown that blood is not a suitable fluid for the detection of tumor-derived biomarkers in patients with CNS malignancies. In contrast, cerebrospinal fluid (CSF), due to its proximity to the brain parenchyma, is a source of informative biomarkers (e.g., circulating tumor DNA (ctDNA) and metabolites). We hypothesize that it is possible to perform pre- operative molecular characterization and monitoring of patients with CNS tumors by analyzing ctDNA and metabolites in the CSF. Moreover, our prediction is that the levels of these biomarkers will correlate with tumor burden. We anticipate that quantification of these biomarkers in the CSF will facilitate monitoring patients with CNS cancer for tumor recurrence and response to therapies. Our preliminary experiments show that we can isolate ctDNA from small volumes of CSF and detect mutations by next generation sequencing (NGS) and droplet digital PCR (ddPCR), at a mutant allele frequency of 0.25% and 0.1%, respectively. We have also identified tumor-specific metabolic signatures in the CSF, and our data shows higher levels of D-2- hydroglyglutarate in the CSF of patients with CNS tumors harboring an IDH1/IDH2 mutation. We propose to pursue two specific aims to develop a CSF-liquid biopsy assay: (1) Validation of a next generation sequencing (NGS) assay to quantify tumor DNA in CSF; (2) To perform metabolomic analysis of ~125 tumor-derived metabolites in CSF. This multi-platform approach will allow comparisons of sensitivity and specificity among various methodologies and cross correlation of results between platforms. Volumetric analysis of CNS lesions in MRI will allow us to evaluate the potential of each biomarker for quantifying CNS tumor burden. We anticipate that these studies will culminate in the clinical implementation of a liquid biopsy assay to facilitate diagnosis and the use of targeted therapies in adult of pediatric patients with primary or metastatic CNS tumors.
项目概要/摘要 原发性和转移性中枢神经系统肿瘤 (CNS) 的发病率很高 和死亡率。需要新的、更有效的诊断、治疗和监测策略 原发性和转移性中枢神经系统肿瘤患者。满足分子生物学需求的方法论 对中枢神经系统患者使用精准医疗和靶向治疗所需的信息 肿瘤,是有限的。液体活检测定将有助于早期分子表征和监测 中枢神经系统肿瘤患者,将彻底改变患者管理。研究表明,血液不是 适用于检测中枢神经系统恶性肿瘤患者肿瘤衍生生物标志物的液体。相比之下, 脑脊液 (CSF) 由于靠近脑实质,是信息丰富的生物标志物的来源 (例如,循环肿瘤 DNA (ctDNA) 和代谢物)。我们假设可以执行预 通过分析 ctDNA 和中枢神经系统肿瘤患者的手术分子特征和监测 脑脊液中的代谢物。此外,我们的预测是这些生物标志物的水平将与肿瘤相关 负担。我们预计脑脊液中这些生物标志物的量化将有助于监测患者 中枢神经系统癌症用于肿瘤复发和治疗反应。我们的初步实验表明我们可以 从少量脑脊液中分离 ctDNA,并通过下一代测序 (NGS) 检测突变 液滴数字 PCR (ddPCR),突变等位基因频率分别为 0.25% 和 0.1%。我们还有 确定了脑脊液中肿瘤特异性代谢特征,我们的数据显示 D-2- 水平较高 携带 IDH1/IDH2 突变的中枢神经系统肿瘤患者脑脊液中的氢甘戊二酸。我们建议 开发脑脊液液体活检检测的两个具体目标是:(1) 验证下一代测序 (NGS) 定量脑脊液中肿瘤 DNA 的测定; (2) 对约 125 种肿瘤来源的物质进行代谢组学分析 脑脊液中的代谢物。这种多平台方法将允许比较不同平台之间的敏感性和特异性。 各种方法和平台之间结果的相互关联。中枢神经系统病变的体积分析 MRI 中的研究将使我们能够评估每种生物标志物量化中枢神经系统肿瘤负荷的潜力。我们 预计这些研究最终将导致液体活检测定的临床实施,以促进 原发性或转移性中枢神经系统成人或儿童患者的诊断和靶向治疗的使用 肿瘤。

项目成果

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Leomar Y Ballester其他文献

Leomar Y Ballester的其他文献

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{{ truncateString('Leomar Y Ballester', 18)}}的其他基金

Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10055321
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10478057
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10261492
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10686901
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:

相似海外基金

Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10055321
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10478057
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10261492
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors
用于中枢神经系统肿瘤患者分子表征和监测的脑脊液液体活检的开发和验证
  • 批准号:
    10686901
  • 财政年份:
    2020
  • 资助金额:
    $ 24.38万
  • 项目类别:
AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物
  • 批准号:
    10013105
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
Supplement to AMP-AD Brain Proteomic Network Enhancement, Validation and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络的补充,增强、验证并转化为 CSF 生物标志物
  • 批准号:
    10406764
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物
  • 批准号:
    10474124
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物
  • 批准号:
    9788998
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物
  • 批准号:
    10475094
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers
AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物
  • 批准号:
    9982481
  • 财政年份:
    2018
  • 资助金额:
    $ 24.38万
  • 项目类别:
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