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