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.

摘要 IDH突变型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 和辐射，它们总是进展为治疗抗性病变，最终成为致命的。独特的 IDH突变型胶质瘤的代谢表型使恶性细胞可能易受几种候选药物的影响 治疗或治疗组合。仍然迫切需要进行可靠的定量监测， 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， 完善个性化治疗。该项目采用分阶段、里程碑驱动的可行性、发现（R61; 目的1-2）和D2-HG作为IDH突变型神经胶质瘤的候选生物标志物的验证分析（R33;目的3-4）。 本研究利用了CNS的神经外科入路，其中CSF入路装置用于临床 可以将管理部署为纵向CSF通路，作为腰椎穿刺的辅助手段。此外，它利用 基于肿瘤组织分析的肿瘤内D2-HG含量和产生的基于肿瘤的基准 和微透析液。 我们假设CSF D2-HG代表IDH的有用监测生物标志物， 突变胶质瘤，以帮助量化治疗反应和确定疾病复发。为了验证这一 假设，我们提出以下目标： 目的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突变型神经胶质瘤将对D2-HG及其质谱进行详细和严格的分析 包括稳定性、精密度、准确度、干扰和技术以及生物学差异 重复测量并基于金标准基准与肿瘤性质相关。 目的2：确定诊断IDH突变型胶质瘤的CSF D2-HG基线阈值，并定义 表明疾病负担改变的最小百分比变化。适当的ROC模型将建立与 和AUC分析来定义IDH突变型胶质瘤的诊断阈值。横断面患者队列将 用于评价D2 HG对治疗和疾病进展的反应性 目的3：作为治疗反应的生物标志物的CSF D2 HG。将评价CSF D2-HG 纵向验证对治疗的反应性，作为基准的改良RANO标准。 目的4：评估CSF D2 HG作为疾病进展的生物标志物。一个累积的横断面队列， 在疾病监测期间，将对经证实的IDH突变型胶质瘤患者进行纵向随访， 疾病，以验证指示疾病进展的限定阈值。