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

摘要 IDH突变型胶质瘤是年轻人最常见的胶质瘤。尽管最初对化疗敏感 和放射，它们总是随着治疗耐药皮损的进展而最终变得致命。独一无二的 IDH突变型胶质瘤的代谢表型使恶性细胞对几种候选药物具有潜在的易感性 治疗或治疗组合。对可靠的定量监测的迫切需求仍未得到满足 生物标记物加速翻译进程，因为疾病病程通常持续数年， 以患者为中心的治疗发现模式可以利用可靠的替代结果进行迭代 个性化治疗的精细化。该项目利用阶段性的、里程碑驱动的可行性、发现(R61； AIMS 1-2)和验证分析(R33；AIMS 3-4)D2-HG作为IDH突变型胶质瘤的候选生物标记物。 这项研究利用了神经外科进入中枢神经系统的优势，其中脑脊液进入装置用于临床 作为腰椎穿刺术的辅助手段，可对纵向脑脊液穿刺术进行管理。此外，它还利用 基于肿瘤组织分析的肿瘤内D2-HG含量和产生的肿瘤基准 和微透析液。 我们推测，脑脊液D2-HG是IDH的一个有用的监测生物标志物。 突变型胶质瘤有助于量化治疗反应并识别疾病复发。为了测试这一点 假设，我们提出了以下目标： 目的1：确定脑脊液D2-HG作为生物标志物的技术和生物学特性 IDH突变的神经胶质瘤。将对D2-HG及其质谱学进行详细和严格的分析 分析包括稳定性、精密度、准确度、干扰以及技术和生物差异。 基于黄金标准基准的重复测量和与肿瘤特性的相关性。 目的2：确定脑脊液D2-HG诊断IDH突变型胶质瘤的基线阈值 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 AUC分析确定IDH突变型胶质瘤的阈值诊断。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 目的3：验证脑脊液D2HG作为疗效生物标志物的有效性。将对CSFD2-HG进行评估 纵向验证对治疗的反应性，作为基准修订的RANO标准。 目的4：评价脑脊液D2HG作为疾病进展的生物标志物。一个累积的横截面队列 确诊为idh突变型胶质瘤的患者将在疾病监测期间进行纵向随访，以确定是否复发。 疾病验证所定义的指示疾病进展的阈值。

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.