Intracranial D-2-Hydroxyglutarate as a Monitoring Biomarker for IDH-mutant Glioma.

颅内 D-2-羟基戊二酸作为 IDH 突变胶质瘤的监测生物标志物。

• 批准号: 10591511
• 负责人: Terry Burns
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591511
• 关键词: Acceleration; Benchmarking; Biochemical Genetics; Biological; Biological Assay; Biological Markers; Bioluminescence; Cellularity; Cerebrospinal Fluid; Characteristics; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Core Facility; Data; Detection; Devices; Diagnosis; Diagnostic; Disease; Disease Progression; Disease Surveillance; Excision; Glioma; Histologic; Human; Image; Individual; Laboratories; Lesion; Linear Regressions; Location; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Microdialysis; Minor; Modeling; Molecular; Monitor; Monitoring for Recurrence; Mus; Newly Diagnosed; Ommaya Reservoir; Operative Surgical Procedures; Outcome; Patients; Performance; Phase; Postoperative Period; Pre-Clinical Model; Production; Progressive Disease; Property; Recurrence; Recurrent disease; Recurrent tumor; Residual Neoplasm; Resistance; Sampling; Sensitivity and Specificity; Series; Site; Spectrum Analysis; Spinal Puncture; Stereoisomer; Testing; Therapeutic; Time; Tumor Tissue; Tumor Volume; Validation; Ventricular; biomarker discovery; burden of illness; cancer cell; candidate marker; cohort; epigenomics; extracellular; follow-up; individual patient; individualized medicine; metabolic phenotype; metabolomics; mutant; neurosurgery; new therapeutic target; radiation effect; radiological imaging; response; survival outcome; translational progress; translational therapeutics; treatment response; tumor; tumor progression; young adult

ABSTRACT IDH-mutant gliomas are the most common gliomas of young adults. Despite initial sensitivity to chemotherapy and radiation, they invariably progress as treatment resistant lesions to become ultimately fatal. The unique metabolic phenotype of IDH-mutant glioma leaves malignant cells potentially vulnerable to several candidate therapies or therapeutic combination. There remains an urgent unmet need for a reliable quantitative monitoring biomarker to accelerate translational progress Since disease course frequently extends over several years, patient-centric models of therapeutic discovery could leverage reliable surrogate outcomes toward iterative refinement of individualized therapies. This project utilizes a phased, milestone-driven feasibility, discovery (R61; Aims 1-2) and validation analysis (R33; Aims 3-4) of D2-HG as a candidate biomarker of IDH-mutant glioma. This study takes advantage of neurosurgical access to the CNS, wherein CSF access devices utilized for clinical management may be deployed for longitudinal CSF access as an adjunct to lumbar puncture. Moreover, it utilizes tumor-based benchmarks for D2-HG content and production within the tumor based on analysis of tumor tissue and microdialysate. We hypothesize that CSF D2-HG represents a useful monitoring biomarker for IDH- mutant glioma to help quantify response to therapy and identify disease recurrence. To test this hypothesis, we propose the following aims: Aim 1: Determine the technical and biological performance characteristics of CSF D2-HG as a biomarker of IDH-mutant glioma. Detailed and rigorous analyses will be performed for D2-HG and its mass spectroscopy assay including stability, precision, accuracy, interference, and technical as well as biological variance upon repeated measurements and correlates to tumor properties based upon gold-standard benchmarks. Aim 2: Determine a baseline threshold value of CSF D2-HG diagnostic for IDH-mutant glioma and define the minimal percent change indicative of altered disease burden. Appropriate ROC models will be built with and AUC analysis to define a threshold diagnostic of IDH-mutant glioma. Cross-sectional patient cohorts will be used to evaluate responsiveness of D2HG to therapy and disease progression Aim 3: Validate CSF D2HG as a biomarker of therapeutic response. CSF D2-HG will be evaluated longitudinally in to validate responsiveness to therapy as benchmarked modified RANO criteria. Aim 4: Evaluate CSF D2HG as a biomarker of disease progression. A cumulative cross-sectional cohort of patients with verified IDH-mutant gliomas will be followed longitudinally during disease monitoring for recurrent disease to validate the defined threshold indicative of disease progression.

抽象的 IDH突变神经胶质瘤是年轻人最常见的神经胶质瘤。尽管对化学疗法的最初敏感 和辐射，它们总是随着耐药性病变的最终致命而发展。独特 IDH-突变神经瘤的代谢表型叶叶恶性细胞可能容易受到几个候选者的影响 疗法或治疗组合。对可靠的定量监控仍然不满意 生物标志物可以加速转化进展，因为疾病病程经常在几年中延长， 以患者为中心的治疗发现模型可以利用可靠的替代结果来迭代 个性化疗法的细化。该项目利用了一个分阶段，里程碑驱动的可行性，发现（R61; 目的1-2）和D2-Hg的验证分析（R33； Aims 3-4）作为IDH突变神经瘤的候选生物标志物。 这项研究利用神经外科访问CNS，其中CSF访问设备用于临床 可以将管理部署用于纵向CSF访问作为腰椎穿刺的辅助手段。而且，它利用了 基于肿瘤组织的分析，基于肿瘤的D2-HG含量和生产基准 和微疗法。 我们假设CSF D2-HG代表了IDH-的有用监测生物标志物 突变神经胶质瘤有助于量化对治疗的反应并鉴定疾病复发。测试这个 假设，我们提出以下目的： 目标1：确定CSF D2-HG作为生物标志物的技术和生物学性能特征 IDH突变神经瘤。将对D2-HG及其质谱进行详细的严格分析 测定包括稳定性，精度，准确性，干扰以及技术以及生物学差异 重复测量并根据金色标准基准与肿瘤性质相关。 AIM 2：确定IDH突变胶质瘤CSF D2-HG诊断的基线阈值并定义 最小的百分比变化表示疾病负担改变。适当的ROC模型将与 和AUC分析以定义IDH突变神经胶质瘤的阈值诊断。横断面患者队列将是 用于评估D2HG对治疗和疾病进展的反应性 AIM 3：验证CSF D2HG作为治疗反应的生物标志物。 CSF D2-HG将评估 纵向以验证对治疗的反应性作为基准改良的RANO标准。 AIM 4：评估CSF D2HG作为疾病进展的生物标志物。累积的横截面队列 经过验证的IDH突变胶质瘤的患者将在疾病监测期间进行纵向跟踪 疾病以验证指示疾病进展的定义阈值。