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）是中枢神经系统最具侵袭性的恶性肿瘤