A microfluidic blood-based test to monitor treatment response in glioblastoma

一种基于血液的微流体测试，用于监测胶质母细胞瘤的治疗反应

• 批准号: 9613031
• 负责人: Brian Vala Nahed
• 金额: $ 45.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9613031
• 关键词: Address; Adverse effects; Biological Assay; Biological Markers; Biology; Biopsy; Blood; Blood - brain barrier anatomy; Blood Tests; Brain Neoplasms; Caring; Cells; Classification; Clinic; Clinical; Clinical Trials; Complement; DNA; Data; Data Set; Detection; Development; Devices; Diagnosis; Diagnostic radiologic examination; Disease; Enrollment; Evolution; Failure; Frequencies; General Hospitals; Genomics; Glioblastoma; Glioma; Goals; Grant; Histologic; Image; Investigational Therapies; Laboratories; Magnetic Resonance Imaging; Malignant Neoplasms; Massachusetts; Microfluidic Microchips; Microfluidics; Molecular; Molecular Genetics; Monitor; Morbidity - disease rate; Mutation; Mutation Analysis; Neoplasm Circulating Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathologic; Patient Care; Patient Monitoring; Patients; Postoperative Period; Prediction of Response to Therapy; Proteins; Proteomics; Protocols documentation; RNA; Radiation necrosis; Radiation therapy; Recurrence; Reproducibility; Sampling; Series; Signal Transduction; Source; Stream; Techniques; Technology; Testing; Time; Tissues; Translating; Tube; Tumor Burden; Vascular Proliferation; base; biomarker discovery; cancer cell; chemoradiation; chemotherapy; chromatin immunoprecipitation; clinically relevant; cohort; cost; design; digital; exosome; experience; extracellular vesicles; genetic information; improved; liquid biopsy; microfluidic technology; minimally invasive; molecular marker; next generation sequencing; novel; particle; patient population; response; response biomarker; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor DNA; tumor progression; vesicular release

PROJECT SUMMARY The diagnosis and monitoring of patients with glioblastoma requires both surgery and magnetic resonance imaging in complement. Surgery critically provides tissue for histological and molecular characterization and MRI facilitates subsequent monitoring despite its limitation to differentiate between treatment response (radiation necrosis) and failure (tumor recurrence). As a result, patients undergo an additional surgical procedure to obtain tissue for molecular characterization, and to distinguish treatment response from failure requiring a change in therapy. Given the morbidity associated with surgery, patients cannot undergo serial biopsies therefore a minimally invasive test would provide real-time analysis and change our understanding and management of glioblastoma. Our laboratory is the first to identify both circulating tumor cells (CTCs) and exosomes (EVs) in the blood of patients with glioblastoma. In other cancers, CTCs and EVs have been independently captured, characterized, and analyzed to provide real-time information of the patient's tumor burden and identifying new mutations that confer resistance to therapy. Despite the blood brain barrier, EVs and CTCs are found in the blood in high and low frequencies. Currently, no existing technology exists to simultaneously capture and monitor both EVs and CTCs in patient blood. Thus, we propose the use of microfluidics to develop and validate our blood based `liquid biopsy' to isolate both EVs and CTCs from a single tube of blood from patients with glioblastoma at diagnosis and throughout treatment. We will also use standard techniques to evaluate ctDNA in parallel to evaluate any additive benefit to our assay. Microfluidic processing of clinical samples is low cost and shows great promise for translating `blood-on-a-chip' assays to the clinic. Our assay will allow for real-time molecular characterization throughout therapy and potentially identify novel treatments or better match patients with existing clinical trials. In addition, we aim to more accurately determine treatment response and inevitable recurrence using next generation sequencing of CTCs, EVs and ctDNA from diagnosis onward; ultimately establishing a minimally invasive test to diagnose, monitor, and detect recurrence in patients with glioblastoma. The new 2016 WHO classification of brain tumors has added molecular markers to the pathological diagnosis of glioblastoma which has traditionally required surgical tissue; we aim through our liquid biopsy to provide the first molecular characterization and classification of brain tumors through a simple blood test in real-time. This will dramatically advance our understanding and the care of patients with glioblastoma.

项目摘要 胶质母细胞瘤患者的诊断和监测需要手术和磁共振 影像互补外科手术为组织学和分子表征以及MRI提供了重要的组织 尽管在区分治疗反应（放射）方面存在局限性，但仍有助于后续监测 坏死）和失败（肿瘤复发）。因此，患者需要接受额外的外科手术， 组织进行分子表征，并区分治疗反应与需要改变的失败， 疗法考虑到与手术相关的发病率，患者不能接受连续活检，因此， 微创检测将提供实时分析，并改变我们对 胶质母细胞瘤我们的实验室是第一个在肿瘤细胞中鉴定循环肿瘤细胞（CTC）和外泌体（EV）的实验室。 胶质母细胞瘤患者的血液。在其他癌症中，CTC和EV已被独立捕获， 表征和分析，以提供患者肿瘤负荷的实时信息， 对治疗产生抗药性的突变。尽管存在血脑屏障，但在血液中发现EV和CTC 高频和低频。目前，不存在同时捕获和监视这两者的现有技术。 患者血液中的EV和CTC。因此，我们建议使用微流体来开发和验证我们的血液 基于“液体活检”从胶质母细胞瘤患者的单管血液中分离EV和CTC 在诊断和整个治疗过程中。我们还将使用标准技术来平行评估ctDNA， 评估对我们的测定的任何附加益处。临床样品的微流体处理是低成本的，并且显示出很大的优势。 承诺将“血液芯片”化验法应用于临床。我们的实验将允许实时分子 在整个治疗过程中进行表征，并可能识别新的治疗方法或更好地匹配患者， 现有的临床试验。此外，我们旨在更准确地确定治疗反应和不可避免的 从诊断开始使用CTC、EV和ctDNA的下一代测序复发;最终 建立一个微创测试，以诊断，监测和检测胶质母细胞瘤患者的复发。 新的2016年WHO脑肿瘤分类在病理诊断中增加了分子标志物， 胶质母细胞瘤传统上需要手术组织;我们的目标是通过我们的液体活检提供第一个 通过简单的实时血液检测对脑肿瘤进行分子表征和分类。这将 极大地促进了我们对胶质母细胞瘤患者的理解和护理。