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

项目总结/摘要 美国约有70万患者患有原发性中枢神经系统肿瘤，约20万患者患有原发性中枢神经系统肿瘤。 每年都有新的脑转移病例被诊断出来。目前诊断脑肿瘤的方法主要是 通过神经成像[例如，磁共振成像（MRI）]以检测具有足够质量的肿瘤， 通过手术切除或立体定向活检对影像学检查结果进行组织学确认。然而，组织 活组织检查具有显著的风险，对于重复取样以监测肿瘤进展是不可行的， 治疗反应，并且可能根本不可能在手术无法触及的肿瘤位置或医学上 不能手术的病人基于血液的液体活检提供了一种非侵入性的方法来分类疾病，指导治疗， 监测治疗反应，并通过检测揭示疾病的分子机制， 循环肿瘤生物标志物（例如，DNA、RNA、细胞外囊泡和肿瘤细胞脱落的蛋白质）。它有 改变了几种脑外癌症的临床治疗。然而，扩大血液基础 对脑癌进行液体活检具有挑战性，主要是因为血脑屏障（BBB）阻碍了转移 肿瘤生物标记物进入血液循环系统。为了克服这一挑战，我们的团队引入了 聚焦超声脑肿瘤液体活检（FUS-LBx）技术， 脑肿瘤的空间靶向分子表征。中心假设是FUS介导的BBB 破坏打开了大脑和血池之间的“双向运输”，从而将大脑生物标志物释放到大脑中。 血液循环以及允许循环药物进入大脑。我们的长期目标是将 通过提供疾病的分子特征来临床管理脑癌患者， 无创FUS-LBx。本申请的目的是获得令人信服的临床前证据， 支持FUS-LBx的未来临床翻译。我们会透过以下三项工作，达致上述目标 具体目标：（1）评价FUS参数对脑肿瘤生物标志物释放水平和安全性的影响 （2）评价肿瘤变量对FUS介导的脑肿瘤的影响 （3）评估FUS-LBx在脑肿瘤小鼠模型中的可行性和安全性。 猪脑肿瘤模型。本研究的创新点主要有三点：（1）提出了FUS- 诱导的血脑屏障破坏使血液和脑之间的双向运输开辟了一个新的研究领域;（2） FUS-LBx是一种创新的诊断工具，为FUS技术的临床转化提供了新的途径; (3)将用于本研究的猪脑肿瘤模型提供了一个大型动物模型，对于 获得支持FUS-LBx临床转化的明确证据。这个项目意义重大 因为这项创新技术具有巨大的潜力，可以从根本上推进大脑的诊断和监测， 癌症患者通过识别肿瘤的分子特征而无需手术。

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.