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

• 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
• 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

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.

摘要 对于非侵入性方法来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存在未满足的关键需求。我们的团队是第一个引入聚焦超声（FUS）启用液体活检技术的脑肿瘤的非侵入性和空间靶向分子诊断和表征，我们称之为声活检。目前超声活检在临床实践中广泛使用的障碍是缺乏严格表征该技术安全性和可行性的人体数据。我们的长期目标是通过使用声活检提供疾病的遗传特征来改变GBM患者的临床管理。本提案的总体目标是进行随机、盲法、双组、单中心前瞻性临床试验，以验证声活检的安全性和诊断可行性。我们有强有力的初步数据，证明了声活检在啮齿动物和猪GBM模型中的可行性和安全性，并开发了一种神经导航引导的FUS系统，用于在患者中进行声活检。所提出的临床试验将实现两个特定目标：1）证明GBM血浆循环肿瘤DNA（ctDNA）的富集到超声活检的可检测水平，以及2）定义超声活检在GBM患者中的安全性特征。在第一个目标下，我们将招募40名术前GBM患者，他们将被随机（1：1）进行超声活检与假手术。在手术切除前即刻，将进行超声活检或假手术，并在超声处理前后采集血浆。将对血浆样本以及手术切除的超声处理肿瘤样本进行基因测序。我们将比较：1）超声活检前和后血液中GBM特异性变体的频率，2）超声活检和假手术之间ctDNA富集的差异，和3）超声活检后血浆样品和肿瘤样品的标准测序之间突变检测的一致性。对于第二个目标，由于超声活检或假干预将在切除前在术中MRI手术室中进行，因此我们将使用MR成像来定义血脑屏障通透性变化，并检测周围健康组织和超声处理部位的组织损伤或水肿/出血（如果发生），将对手术切除的超声处理和未超声处理的肿瘤进行组织学分析，以通过对出血、坏死、细胞凋亡进行染色，和炎症标志物。该项目是创新的，因为它是一个实质性的背离现状，通过使用FUS以一种新的方式，大大增加血液中肿瘤生物标志物的存在。这项研究意义重大，因为它将建立知识基础，使这项创新技术能够转化，并最终通过识别肿瘤的遗传特征而无需手术来推进脑癌患者的诊断和监测。除了解剖成像和手术组织学的标准诊断外，声活检有可能成为脑肿瘤管理的第三大支柱，这将对患者的生存和生活质量产生巨大影响。