Focused ultrasound-enabled brain tumor liquid biopsy (FUS-LBx)

聚焦超声脑肿瘤液体活检 (FUS-LBx)

• 批准号: 10225466
• 负责人: Hong Chen
• 金额: $ 62.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225466
• 关键词: Acoustics; Affect; Animal Model; Automobile Driving; Behavior; Benchmarking; Biological Markers; Biopsy; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Diseases; Brain Neoplasms; Brain Stem; Cancer Patient; Cardiovascular system; Cells; Central Nervous System Neoplasms; Clinical Management; Collection; Corpus striatum structure; DNA; Data; Dependence; Detection; Diagnosis; Diagnostic; Diffuse intrinsic pontine glioma; Disease; Epidermal Growth Factor Receptor; Excision; Family suidae; Focused Ultrasound; Future; Gene Mutation; Glioblastoma; Goals; Green Fluorescent Proteins; Growth; Hemorrhage; Histologic; Human; Image; Intravenous; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Medical; Messenger RNA; Metastatic malignant neoplasm to brain; Microbubbles; Modeling; Molecular; Molecular Profiling; Molecular Target; Monitor; Mus; Operative Surgical Procedures; Pathway interactions; Patient Care; Patient Monitoring; Patients; Pharmaceutical Preparations; Plasma; Proteins; Public Health; RNA; Research; Risk; Safety; Sampling; Scanning; Site; System; Techniques; Technology; Testing; Therapeutic Agents; Tissues; Tumor Markers; Tumor-Derived; United States; Variant; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain parenchyma; cell free DNA; clinical translation; extracellular vesicles; implantation; innovation; innovative technologies; liquid biopsy; mouse model; neoplastic cell; neuroimaging; novel; pre-clinical; predictive marker; pressure; protein biomarkers; safety and feasibility; tool; trafficking; treatment response; tumor; tumor progression; Acoustics; Affect; Animal Model; Automobile Driving; Behavior; Benchmarking; Biological Markers; Biopsy; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Diseases; Brain Neoplasms; Brain Stem; Cancer Patient; Cardiovascular system; Cells; Central Nervous System Neoplasms; Clinical Management; Collection; Corpus striatum structure; DNA; Data; Dependence; Detection; Diagnosis; Diagnostic; Diffuse intrinsic pontine glioma; Disease; Epidermal Growth Factor Receptor; Excision; Family suidae; Focused Ultrasound; Future; Gene Mutation; Glioblastoma; Goals; Green Fluorescent Proteins; Growth; Hemorrhage; Histologic; Human; Image; Intravenous; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Medical; Messenger RNA; Metastatic malignant neoplasm to brain; Microbubbles; Modeling; Molecular; Molecular Profiling; Molecular Target; Monitor; Mus; Operative Surgical Procedures; Pathway interactions; Patient Care; Patient Monitoring; Patients; Pharmaceutical Preparations; Plasma; Proteins; Public Health; RNA; Research; Risk; Safety; Sampling; Scanning; Site; System; Techniques; Technology; Testing; Therapeutic Agents; Tissues; Tumor Markers; Tumor-Derived; United States; Variant; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain parenchyma; cell free DNA; clinical translation; extracellular vesicles; implantation; innovation; innovative technologies; liquid biopsy; mouse model; neoplastic cell; neuroimaging; novel; pre-clinical; predictive marker; pressure; protein biomarkers; safety and feasibility; tool; trafficking; treatment response; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Approximately 700,000 patients in the United States have a primary central nervous system tumor, and ~200,000 new cases of brain metastases are diagnosed annually. The current approach for brain tumor diagnosis is mainly through neuroimaging [e.g., magnetic resonance imaging (MRI)] to detect tumors with sufficient mass followed by surgical resection or stereotactic biopsy for histologic confirmation of imaging findings. However, tissue biopsies carry significant risk, are not feasible for repeated sampling to monitor the tumor progression and treatment response, and may not be possible at all in surgically inaccessible tumor locations or medically inoperable patients. Blood-based liquid biopsy offers a noninvasive approach to classify disease, guide therapy, monitor treatment response, and unravel molecular mechanisms underlying the disease through the detection of circulating tumor biomarkers (e.g., DNA, RNA, extracellular vesicles, and proteins shed by tumor cells). It has transformed the clinical management of several cancers outside the brain. However, extending blood-based liquid biopsies to brain cancer is challenging mainly because the blood-brain barrier (BBB) hinders the transfer of tumor-derived biomarkers into the blood circulation system. To overcome this challenge, our group introduced the focused ultrasound-enabled brain tumor liquid biopsy (FUS-LBx) technique for noninvasive and spatially targeted molecular characterization of brain tumors. The central hypothesis is that FUS-mediated BBB disruption opens “two-way trafficking” between brain and blood pool, thereby releasing brain biomarkers into the blood circulation as well as allowing circulating drugs to enter the brain. Our long-term goal is to transform the clinical management of patients with brain cancer by providing molecular signatures of the disease using noninvasive FUS-LBx. The objective of this application is to obtain compelling preclinical evidence needed to support future clinical translation of FUS-LBx. Our objective will be achieved by completing the following three specific aims: (1) Evaluate the impact of FUS parameters on brain-tumor biomarker-release levels and safety in a mouse brain tumor model; (2) Evaluate the impact of tumor variables on FUS-mediated brain-tumor biomarker-release levels in mouse models of brain tumors; (3) Assess the feasibility and safety of FUS-LBx in a pig brain tumor model. The proposed research contains three main innovations: (1) The hypothesis that FUS- induced BBB disruption enables two-way trafficking between blood and brain opens a new research field; (2) FUS-LBx is an innovative diagnostic tool and provides a new pathway to clinical translation of FUS technology; (3) The pig brain tumor model that will be used in this study provides a large animal model that is critical for obtaining unequivocal evidence to support the clinical translation of FUS-LBx. This project is significant because this innovative technique has great potential to radically advance the diagnosis and monitoring of brain cancer patients by identifying molecular signatures of the tumor without surgery.

项目摘要/摘要 美国大约有70万名患者患有原发性中枢神经系统肿瘤，约20万名 每年诊断出新的脑转移病例。当前的脑肿瘤诊断方法主要是 通过神经成像[ 通过手术切除或立体定向活检，用于对成像发现的组织学证实。但是，组织 活检有重大风险，对于重复采样以监测肿瘤进展和 治疗反应，在手术无法访问的肿瘤位置或医学上可能根本不可能 无法手术的患者。基于血液的液体活检提供了一种无创的方法来分类疾病，指导治疗， 监测治疗反应，并通过检测来揭示疾病潜在的分子机制 循环肿瘤生物标志物（例如DNA，RNA，细胞外蔬菜和肿瘤细胞脱离的蛋白质）。它有 改变了大脑外几种癌症的临床管理。但是，扩展基于血液 脑癌的液体活检主要是因为血脑屏障（BBB）阻碍了转移 肿瘤来源的生物标志物进入血液循环系统。为了克服这一挑战，我们的小组介绍了 针对非侵入性和无创和 脑肿瘤的空间靶向分子表征。中心假设是FUS介导的BBB 破坏在大脑和血液库之间打开“双向贩运”，从而将脑生物标志物释放到 血液循环以及允许循环药物进入大脑。我们的长期目标是改变 通过使用使用分子特征来使用该疾病的分子特征来对患有脑癌患者的临床管理 非侵入性FUS-LBX。该应用的目的是获得所需的令人信服的临床前证据 支持FUS-LBX的未来临床翻译。我们的目标将通过完成以下三个来实现 具体目的：（1）评估FUS参数对脑肿瘤生物标志物释放水平和安全性的影响 在小鼠脑肿瘤模型中； （2）评估肿瘤变量对FUS介导的脑肿瘤的影响 脑肿瘤小鼠模型中的生物标志物释放水平； （3）评估FUS-LBX在A中的可行性和安全性 猪脑肿瘤模型。拟议的研究包含三个主要创新：（1）假设FUS- 诱导的BBB破坏使血液和大脑之间的双向贩运开设了一个新的研究领域。 （2） FUS-LBX是一种创新的诊断工具，为FUS技术的临床翻译提供了新的途径； （3）本研究中将使用的猪脑肿瘤模型提供了一个大型动物模型，这对于 获得明确的证据以支持FUS-LBX的临床翻译。这个项目很重要 因为这种创新技术具有从根本上推进大脑诊断和监测的巨大潜力 癌症患者通过鉴定肿瘤的分子信号而无需手术。