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
• 负责人: Leomar Y Ballester
• 金额: $ 26.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686901
• 关键词: Address; Adult; Affect; Biological Assay; Biological Markers; Biopsy; Blood; Brain Neoplasms; Central Nervous System Neoplasms; Cerebrospinal Fluid; Clinical; Collection; Data; Detection; Development; Diagnosis; Gene Frequency; Genes; Glioma; Lesion; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Molecular; Monitor; Morbidity - disease rate; Mutate; Mutation; Mutation Detection; Neoplasm Metastasis; Neoplasms; Nucleic Acids; Oncogenic; Patient Monitoring; Patients; Primary Neoplasm; Production; Public Health; Recurrent tumor; Research; Sampling; Sensitivity and Specificity; Source; Tissue Sample; Tissues; Tumor Burden; Tumor Tissue; Tumor Volume; Tumor-Derived; Validation; assay development; brain parenchyma; brain surgery; cancer cell; cancer type; clinical implementation; clinical practice; digital; effective therapy; experimental study; innovation; liquid biopsy; metabolomics; mortality; mutant; next generation sequencing; novel; novel strategies; pediatric patients; precision medicine; repository; targeted treatment; treatment response; tumor; tumor DNA

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.

项目摘要/摘要 原发和转移性中枢神经系统肿瘤(CNS)发病率高 和死亡率。需要新的、更有效的诊断、治疗和监测战略。 原发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学 中枢神经系统患者使用精确医学和靶向治疗所需的信息 肿瘤是有限的。液体活组织检查将有助于早期分子表征和监测 这将使患者管理发生革命性变化。研究表明，血液不是一种 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)由于其接近脑实质，是信息性生物标志物的来源。 (例如，循环肿瘤DNA(CtDNA)和代谢物)。我们假设有可能进行预先- 应用ctDNA和ctDNA分析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的 中枢神经系统癌对肿瘤复发和治疗的反应。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)和 Droplet Digital PCR(DdPCR)，突变等位基因频率分别为0.25%和0.1%。我们还有 在脑脊液中发现了肿瘤特异的代谢特征，我们的数据显示D-2- 携带IDH1/IDH2突变的中枢神经系统肿瘤患者脑脊液中的羟基戊二酸我们建议 追求两个特定的目标来开发脑脊液-液体活组织检查：(1)下一代测序的验证 (2)进行~125肿瘤来源的代谢组学分析 脑脊液中的代谢物。这种多平台方法将允许对以下各项的敏感性和特异性进行比较 各种方法和平台之间结果的交叉关联。中枢神经系统病变的体积分析 磁共振成像将使我们能够评估每个生物标记物在量化中枢神经系统肿瘤负担方面的潜力。我们 预计这些研究将最终在临床上实施液体活组织检查，以促进 成人原发或转移性中枢神经系统疾病的诊断和靶向治疗 肿瘤。

项目成果

Hormone exposure and its suppressive effect on risk of high-grade gliomas among patients with breast cancer.

• DOI: 10.1016/j.jocn.2021.10.029
• 发表时间: 2021-12
• 期刊: JOURNAL OF CLINICAL NEUROSCIENCE
• 影响因子: 2
• 作者: Lopez-Garcia, Carlos A.;Lopez-Rivera, Victor;Dono, Antonio;Salazar-Marioni, Sergio;Novo, Jorge E.;Sheth, Sunil A.;Ballester, Leomar Y.;Esquenazi, Yoshua
• 通讯作者: Esquenazi, Yoshua

The genomic alterations in glioblastoma influence the levels of CSF metabolites.

• DOI: 10.1186/s40478-024-01722-1
• 发表时间: 2024-01-19
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

• DOI: 10.1007/s11060-021-03917-1
• 发表时间: 2022-01
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Dono, Antonio;Zhu, Ping;Holmes, Emma;Takayasu, Takeshi;Zhu, Jay-Jiguang;Blanco, Angel, I;Hsu, Sigmund;Bhattacharjee, Meenakshi B.;Ballester, Leomar Y.;Kim, Dong H.;Esquenazi, Yoshua;Tandon, Nitin
• 通讯作者: Tandon, Nitin

Intracranial mesenchymal tumor, FET::CREB fusion-positive in the lateral ventricle.

• DOI: 10.1093/noajnl/vdad026
• 发表时间: 2023-01
• 期刊: Neuro-oncology advances

The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma.

• DOI: 10.1093/noajnl/vdab050
• 发表时间: 2021-01
• 期刊: Neuro-oncology advances
• 作者: Dono A;Ramesh AV;Wang E;Shah M;Tandon N;Ballester LY;Esquenazi Y
• 通讯作者: Esquenazi Y