Imaging and Liquid Biopsy for Glioma Diagnosis and Treatment Monitoring

用于神经胶质瘤诊断和治疗监测的成像和液体活检

• 批准号: 10565900
• 负责人: Bob S Carter
• 金额: $ 60.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565900
• 关键词: Address; Adopted; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Blood specimen; Brain Neoplasms; Caring; Cell Line; Cells; Central Nervous System; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Drug resistance; Early Diagnosis; Ensure; Evolution; Excision; General Hospitals; Glioma; Goals; Heterogeneity; Human; Image; Industry; Laboratories; Longitudinal Studies; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Massachusetts; Mean Survival Times; Measures; Membrane; Messenger RNA; Methods; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Nucleic Acids; Operative Surgical Procedures; Outcome; Outcomes Research; Patients; Performance; Progression-Free Survivals; Protein Analysis; Proteins; Quality Control; Radiation therapy; Readiness; Regression Analysis; Reproducibility; Resistance; Resistance development; Resources; Risk; Sampling; Sampling Biases; Sampling Errors; Specificity; Specimen; Standardization; Systems Biology; Testing; Time; Tissues; Translations; Treatment outcome; Tumor Burden; Vesicle; biobank; cancer biomarkers; cancer cell; chemotherapy; clinical care; clinical diagnostics; clinical translation; cohort; comorbidity; comparative efficacy; design; diagnostic strategy; diagnostic value; digital; exosome; experience; extracellular vesicles; follow-up; improved; individualized medicine; innovation; instrument; liquid biopsy; mRNA Expression; minimally invasive; molecular subtypes; multidisciplinary; nanoscale; new technology; novel; particle; patient stratification; peripheral blood; plasmonics; predictive modeling; pressure; prognostic; programs; screening; statistics; success; technology validation; temozolomide; therapy resistant; tool; translational impact; treatment response; treatment strategy; tumor; tumor heterogeneity; tumor progression

Malignant gliomas (MG) are the most aggressive malignancy of the central nervous system with the mean survival time of 15 months. Fast progression and high heterogeneity of MG mandates frequent imaging (MRI) to measure therapeutic responses. Imaging alone, however, is limited by false positives (“pseudoprogression”) and lacks molecular specificity. Tissue analyses could augment imaging results, but carries the risk of comorbidity and sampling errors. The goal of this project is to address such challenges and advance a minimally invasive, hence serially repeatable clinical assay specific to MG. We will exploit extracellular vesicles (EVs) as a new class of circulating cancer biomarker. Increasing number of studies evidence EVs' potential utility: these vesicles, are released from all cells, function as reliable cellular surrogates and reflect global tumor burden, overcoming limitations of tumor heterogeneity and sampling bias. We now seek to establish a translational EV assay for MG diagnosis and treatment monitoring, and compare its performance with gold standard imaging-based diagnostics. First, we will standardize EV assay protocols for clinical workflow. We will adopt our validated technologies: ExoLution, a clinical grade kit for EV isolation; Shahky, a high-throughput plasmonic instrument for EV protein analyses; and digital droplet PCR for highly sensitive EV mRNA detection. Leveraging the developmental and regulatory expertise of Exosome Diagnostics, we will make these platforms ready for translation into clinical diagnostic laboratories. Second, we will perform a targeted clinical study, critically assessing EVs' diagnostic and prognostic capacity for GBM. We will collect circulating EVs from GBM patients undergoing therapies and monitor serial changes of EV protein/mRNA profiles, particularly to detect the early sign of acquired resistance. We will compare results from EV assays and accompanying MRI, and build an integrative model for treatment monitoring. We formed a powerful multidisciplinary team to conduct these projects: Brain Tumor Center at Massachusetts General Hospital (MGH) which operates a vast biobank program of human clinical samples; Center for Systems Biology at MGH, a pioneer in developing new technologies for EV analyses; and Exosome Diagnostics, a de-facto industry leader in EV-based liquid biopsy with extensive experience in assay standardization. Collectively, the team has a track record of studying EVs' potential as a gliomas biomarker and has established optimal EV assays for molecular analyses. We will ensure assay reliability and reproducibility to deliver clinically translatable EV tests. We will also impose stringent quality controls on assay design and sample processing, accrue well-annotated patient and control samples, and perform statistically powered clinical studies. The technical and scientific outcomes of this research could have a significant translational impact in gliomas care by establishing a robust and highly specific clinical tool for gliomas diagnostics and treatment monitoring.

恶性胶质瘤（MG）是中枢神经系统中最具侵袭性的恶性肿瘤，平均发病率 MG 的快速进展和高度异质性需要频繁的影像学检查 (MRI)，生存时间为 15 个月。 然而，仅靠成像来测量治疗反应受到假阳性（“假进展”）的限制。 且缺乏分子特异性。组织分析可以增强成像结果，但存在以下风险： 该项目的目标是应对此类挑战并推进 我们将利用细胞外技术进行针对 MG 的微创、可连续重复的临床测定。 越来越多的研究证明囊泡（EV）是一类新型循环癌症生物标志物。 潜在效用：这些囊泡从所有细胞中释放出来，作为可靠的细胞替代物发挥作用，并反映 全球肿瘤负担，克服肿瘤异质性和抽样偏差的局限性。 建立用于 MG 诊断和治疗监测的转化 EV 测定，并比较其性能 首先，我们将标准化临床 EV 检测方案。 我们将采用经过验证的技术：ExoLution，一种用于 EV 隔离的临床级试剂盒； 用于 EV 蛋白分析的高通量等离子体仪器；以及用于高灵敏度 EV 的数字液滴 PCR 利用外泌体诊断的开发和监管专业知识，我们将 使这些平台准备好转化为临床诊断实验室。 我们将收集有针对性的临床研究，严格评估 EV 对 GBM 的诊断和预后能力。 接受治疗的 GBM 患者的循环 EV 并监测 EV 蛋白/mRNA 的系列变化 谱，特别是检测获得性耐药的早期迹象，我们将比较 EV 检测的结果。 以及伴随的 MRI，并建立了治疗监测的综合模型。 开展这些项目的多学科团队：马萨诸塞州总医院脑肿瘤中心 (MGH) 运营着一个庞大的人类临床样本生物库项目； MGH，开发 EV 分析新技术的先驱；以及 Exosome Diagnostics，事实上的外泌体诊断 基于 EV 的液体活检行业领导者，在检测标准化方面拥有丰富的经验。 团队拥有研究 EV 作为神经胶质瘤生物标志物潜力的记录，并已建立最佳 EV 我们将确保临床交付的检测可靠性和重现性。 我们还将对检测设计和样品处理实施严格的质量控制， 积累注释良好的患者和对照样本，并进行专业的临床研究。 这项研究的技术和科学成果可能对神经胶质瘤产生重大转化影响 通过建立用于神经胶质瘤诊断和治疗监测的强大且高度特异性的临床工具来提供护理。