Sonobiopsy for Noninvasive Genetic Evaluation of Glioblastoma Patients

声活检对胶质母细胞瘤患者进行无创基因评估

基本信息

批准号：
10564014
负责人：
Hong Chen
金额：
$ 65.12万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564014
关键词：
Animals Apoptosis Biological Markers Biopsy Blinded Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Neoplasms Cancer Detection Cancer Patient Cardiovascular system Cells Cephalic Classification Clinic Clinical Clinical Management Clinical Research Clinical Trials DNA Data Data Analyses Development Devices Diagnosis Diagnostic Disease Drug Delivery Systems Edema Enrollment Evaluation Excision Family suidae Focused Ultrasound Foundations Frequencies Future Genetic Genomics Glioblastoma Goals Green Fluorescent Proteins Hemorrhage Histologic Histology Image Injury Intervention Intravenous Knowledge Location Magnetic Resonance Imaging Malignant neoplasm of brain Measurement Medical Messenger RNA Methods Microbubbles Modeling Molecular Molecular Diagnosis Molecular Profiling Molecular Target Monitor Morbidity - disease rate Mutation Mutation Detection Necrosis Neuronavigation Operative Surgical Procedures Patients Plasma Procedures Property Public Health Quality of Care Quality of life RNA Randomized Research Resected Risk Rodent Safety Sampling Schedule Site Sonication Specimen Stains System Techniques Therapeutic Time Tissues Transfection Translations Tumor Markers Tumor-Derived Variant anatomic imaging blood-brain barrier disruption blood-brain barrier permeabilization circulating biomarkers clinical practice clinically significant detection sensitivity genetic information genetic signature human data implantation improved inflammatory marker innovation liquid biopsy minimally invasive molecular marker mouse model novel personalized care porcine model prospective protein biomarkers radiological imaging safety and feasibility targeted treatment therapeutically effective tissue injury tool treatment response tumor tumor DNA tumor progression

项目摘要

ABSTRACT There is an unmet critical need for noninvasive methods to interrogate the genetic and molecular properties of the malignant brain tumor known as glioblastoma (GBM). Our group was the first to introduce the focused ultrasound (FUS)-enabled liquid biopsy technique for noninvasive and spatially targeted molecular diagnosis and characterization of brain tumors, which we term sonobiopsy. The current barrier to the widespread use of sonobiopsy in clinical practice is the lack of human data that rigorously characterizes the safety and feasibility of this technique. Our long-term goal is to transform the clinical management of GBM patients by providing genetic signatures of the disease using sonobiopsy. The overall obiective of this proposal is to perform a randomized, blinded, double-armed, single-center prospective clinical trial to validate the safety and diagnostic feasibility of sonobiopsy. We have strong preliminary data that demonstrated the feasibility and safety of sonobiopsy in rodent and porcine GBM models and also developed a neuronavigation-guided FUS system for performing sonobiopsy in patients. The proposed clinical trial will accomplish two specific aims: 1) Demonstrate enrichment of GBM plasma circulating tumor DNA (ctDNA) to a detectable level with sonobiopsy and 2) Define the safety profile of sonobiopsy in GBM patients. Under the first aim, we will enroll forty presurgical GBM patients who will be randomized (1 :1) for sonobiopsy versus sham. Immediately prior to surgical resection, sonobiopsy or sham will be performed, and plasma will be collected pre- and post-sonication. Genetic sequencing will be performed on plasma samples, as well as surgically resected sonicated tumor samples. We will compare: 1) the frequency of GBM-specific variants in the blood pre- and post-sonobiopsy, 2) the differences in ctDNA enrichment between sonobiopsy and sham, and 3) the concordance in mutation detection between post-sonobiopsy plasma samples and standard sequencing of tumor samples. For the second aim, because the sonobiopsy or sham intervention will be performed in an intraoperative MRI surgical suite prior to resection, we will use MR imaging to define the blood-brain barrier permeability changes and detect tissue injury or edema/hemorrhage at the surrounding healthy tissue and sonicated sites if they occur, Histological analysis of surgically resected sonicated and un-sonicated tumors will be performed to define the safety profile of sonobiopsy by staining for hemorrhage, necrosis, apoptosis, and inflammation markers. This project is innovative because it is a substantial departure from the status quo by using FUS in a novel fashion to substantially increase the presence of tumor biomarkers in the blood. The proposed research is significant because it will establish the foundation of knowledge to enable the translation of this innovative technique and ultimately advance the diagnosis and monitoring of brain cancer patients by identifying genetic signatures of the tumor without surgery. In addition to the standard diagnostics of anatomic imaging and surgical histology, sonobiopsy has the potential to become the third pillar for brain tumor management which will have a dramatic impact on patient survival and quality of life.

抽象的对非侵入性方法的迫切需要，询问称为胶质母细胞瘤（GBM）的恶性脑肿瘤的遗传和分子特性。我们的小组是第一个引入聚焦超声（FUS）液体活检技术，用于非侵入性和空间靶向的分子诊断和脑肿瘤的表征，我们将其称为Sonobiopsy。当前在临床实践中广泛使用声读物的障碍是缺乏严格表征该技术安全性和可行性的人类数据。我们的长期目标是通过使用Sonobiopsy提供疾病的遗传学特征来改变GBM患者的临床管理。该提案的总体构造是进行一项随机，盲目，双臂单中心的前瞻性临床试验，以验证Sonobiopsy的安全性和诊断性可行性。我们有强大的初步数据，证明了啮齿动物和猪GBM模型的Sonobiopsy的可行性和安全性，并且还开发了一种神经驱动引导的FUS FUS系统，用于对患者进行索诺自肠脑的进行。拟议的临床试验将实现两个具体的目的：1）证明GBM血浆循环肿瘤DNA（CTDNA）的富集在可检测的水平上富含Sonobiopsy和2）定义了GBM患者的Sonobiopsy的安全性。在第一个目标下，我们将招募四十个前术的GBM患者，他们将被随机分组（1：1），以进行超声检查与假手术。在手术切除之前，将进行超声检查或假手术，并将血浆收集前后。遗传测序将在血浆样品以及手术切除的超声肿瘤样品上进行。我们将比较：1）血液前后血液中的GBM特异性变体的频率，2）Sonobiopsy和Sham之间的CtDNA富集差异，以及3）3）突变检测后染料后血浆样品和肿瘤样品标准测序的一致性。为了第二个目标，因为在切除前将在术中的MRI手术套件中在术中进行心脏病检查或虚假干预，我们将使用MR成像来定义血脑屏障的渗透率变化，并检测组织损伤或在周围的健康组织中进行的供应，并在调查中进行供应，并在调查中进行供应，并在调查中进行供应，并进行渗透性均匀分析，并进行渗透性的疾病，并进行了渗透性分析，并进行了依次分析。通过出血，坏死，凋亡和炎症标记的染色，可以通过染色来对安全性的安全性。该项目具有创新性，因为它通过以新颖的方式使用FUS来大大增加血液中肿瘤生物标志物的存在，这与现状大大不同。拟议的研究很重要，因为它将建立知识的基础，以使这种创新技术的翻译能够通过鉴定肿瘤的遗传特征而无需手术，并最终促进对脑癌患者的诊断和监测。除了解剖成像和外科组织学的标准诊断外，Sonobiopsy还具有成为脑肿瘤管理的第三个支柱，这将对患者的存活和生活质量产生巨大影响。