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.

抽象的 对非侵入性方法来探究恶性脑肿瘤（称为胶质母细胞瘤（GBM））的遗传和分子特性的迫切需求尚未得到满足。我们的团队率先推出了聚焦超声（FUS）液体活检技术，用于脑肿瘤的无创和空间靶向分子诊断和表征，我们称之为声活检。目前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的安全性和可行性的人体数据。我们的长期目标是通过声活检提供疾病的遗传特征，从而改变 GBM 患者的临床管理。该提案的总体目标是进行一项随机、盲法、双臂、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。我们拥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，用于对患者进行声活检。拟议的临床试验将实现两个具体目标：1) 证明 GBM 血浆循环肿瘤 DNA (ctDNA) 富集到超声活检可检测的水平，2) 确定超声活检在 GBM 患者中的安全性。根据第一个目标，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。在手术切除之前，将进行超声活检或假手术，并在超声处理之前和之后收集血浆。将对血浆样本以及手术切除的超声肿瘤样本进行基因测序。我们将比较：1）超声活检前后血液中 GBM 特异性变异的频率，2）超声活检与假手术之间 ctDNA 富集的差异，以及 3）超声活检后血浆样本与肿瘤样本标准测序之间突变检测的一致性。对于第二个目标，由于超声活检或假手术干预将在切除前在术中 MRI 手术套件中进行，因此我们将使用 MR 成像来定义血脑屏障渗透性变化，并检测周围健康组织和超声处理部位（如果发生）的组织损伤或水肿/出血，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，以确定血脑屏障通透性变化。 通过出血、坏死、细胞凋亡和炎症标志物染色来确定声活检的安全性。该项目具有创新性，因为它与现状有很大不同，它以一种新颖的方式使用 FUS 来大幅增加血液中肿瘤生物标志物的存在。拟议的研究意义重大，因为它将奠定知识基础，使这种创新技术得以转化，并最终通过在不进行手术的情况下识别肿瘤的遗传特征来推进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之外，声活检有潜力成为脑肿瘤治疗的第三个支柱，这将对患者的生存和生活质量产生巨大影响。