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.

恶性神经胶质瘤（mg）是中枢神经系统中最具侵略性的恶性肿瘤 生存时间为15个月。 MG授权的快速进展和高异质性经常成像（MRI） 测量热反应。然而，仅成像就受到误报的限制（“伪造”） 并且缺乏分子特异性。组织分析可能会增加成像结果，但具有 合并症和采样错误。该项目的目的是应对此类挑战并促进 最小的侵入性，因此串行可重复的临床评估特定于Mg。我们将利用细胞外 蔬菜（EV）是新的循环癌生物标志物。越来越多的研究证据 潜在的实用程序：这些蔬菜从所有细胞中释放出来，作为可靠的细胞替代物的作用并反映 全球肿瘤伯恩，克服肿瘤异质性和采样偏差的局限性。我们现在寻求 建立用于MG诊断和治疗监测的转化EV分析，并比较其性能 具有基于黄金标准成像的诊断。首先，我们将标准化临床EV分析方案 工作流程。我们将采用经过验证的技术：Exolution，一种用于电动汽车隔离的临床级套件； Shahky， 用于电动汽车蛋白分析的高通量血浆仪器；和用于高敏感EV的数字液滴PCR mRNA检测。利用外泌体诊断的发展和法规专业知识，我们将 使这些平台准备转换为临床诊断实验室。第二，我们将执行 有针对性的临床研究，严格评估EVS的GBM诊断和预后能力。我们将收集 来自接受疗法的GBM患者的循环电动汽车并监测EV蛋白/mRNA的串行变化 剖面，特别是检测获得抗性的早期迹象。我们将比较电动汽车分析的结果 并参与MRI，并建立一个用于治疗监测的综合模型。我们形成了一个强大的 多学科团队进行这些项目：马萨诸塞州综合医院的脑肿瘤中心 （MGH）运营着大量的人类临床样品计划；系统生物学中心 MGH，开发新技术进行电动汽车分析的先驱；和外泌体诊断，一种事实上的诊断 基于EV的液体活检的行业领导者，具有丰富的测定标准化经验。集体， 团队具有研究EVS作为神经胶质瘤生物标志物的潜力的记录，并建立了最佳EV 分子分析的测定。我们将确保评估可靠性和可重复性以在临床上提供 可翻译的电动汽车测试。我们还将对测定设计和样品处理施加严格的质量控制， 积累良好的患者和对照样本，并进行统计驱动的临床研究。 这项研究的技术和科学成果可能会对神经胶质瘤产生重大的翻译影响 通过建立一个可用于神经胶质瘤诊断和治疗监测的强大且高度特定的临床工具来护理。