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: 10358421
• 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/10358421
• 关键词: 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; Gold; 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; Mus; Newly Diagnosed; Ommaya Reservoir; Operative Surgical Procedures; Outcome; Patients; Performance; Phase; Postoperative Period; Pre-Clinical Model; Production; Progressive Disease; Property; Recurrence; Recurrent disease; Residual Tumors; Resistance; Sampling; Sensitivity and Specificity; Series; Site; Spectrum Analysis; Spinal Puncture; Stereoisomer; Testing; Therapeutic; Time; Translations; Tumor Tissue; Tumor Volume; Validation; Ventricular; base; biomarker discovery; burden of illness; cancer cell; candidate marker; cohort; epigenomics; extracellular; follow-up; individual patient; individualized medicine; metabolic phenotype; metabolomics; mutant; new therapeutic target; radiation effect; radiological imaging; response; survival outcome; translational progress; 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。尽管最初对化疗敏感 和放射治疗，它们总是会进展为治疗耐药性病变，最终致命。独特的 IDH突变神经胶质瘤的代谢表型使恶性细胞可能容易受到几种候选者的影响 疗法或治疗组合。对可靠的定量监测的迫切需求仍然未得到满足 加速转化进展的生物标志物 由于病程经常延续数年， 以患者为中心的治疗发现模型可以利用可靠的替代结果进行迭代 个体化治疗的细化。该项目采用分阶段、里程碑驱动的可行性、发现（R61； D2-HG 作为 IDH 突变神经胶质瘤的候选生物标志物的目标 1-2）和验证分析（R33；目标 3-4）。 本研究利用神经外科手术进入中枢神经系统，其中脑脊液进入装置用于临床 管理可以作为腰椎穿刺的辅助手段用于纵向脑脊液通路。此外，它利用 基于肿瘤组织分析的肿瘤内 D2-HG 含量和产量的肿瘤基准 和微透析液。 我们假设 CSF D2-HG 代表了一种有用的 IDH-监测生物标志物 突变神经胶质瘤有助于量化治疗反应并识别疾病复发。为了测试这个 假设，我们提出以下目标： 目标 1：确定 CSF D2-HG 作为生物标志物的技术和生物性能特征 IDH 突变神经胶质瘤。将对 D2-HG 及其质谱进行详细而严格的分析 测定包括稳定性、精密度、准确性、干扰以及技术和生物学差异 重复测量并根据黄金标准基准与肿瘤特性相关联。 目标 2：确定 IDH 突变神经胶质瘤的 CSF D2-HG 诊断基线阈值并定义 表明疾病负担改变的最小百分比变化。将建立适当的 ROC 模型 和 AUC 分析以确定 IDH 突变神经胶质瘤的诊断阈值。横断面患者队列将 用于评估 D2HG 对治疗和疾病进展的反应 目标 3：验证 CSF D2HG 作为治疗反应的生物标志物。将评估 CSF D2-HG 纵向验证治疗的反应性作为基准修改的 RANO 标准。 目标 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 经证实的 IDH 突变神经胶质瘤患者将在疾病监测期间进行纵向随访，以发现复发情况 疾病以验证指示疾病进展的定义阈值。