MRgFUS-enabled non-invasive interrogation of malignant glioma via circulating tumor DNA

MRgFUS 通过循环肿瘤 DNA 对恶性神经胶质瘤进行无创检查

• 批准号: 9808152
• 负责人: CHETAN BETTEGOWDA
• 金额: $ 45.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808152
• 关键词: Address; Adult; Animal Model; Animals; Biopsy; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Brain Neoplasms; Cancer Patient; Cerebrospinal Fluid; Chromosome Deletion; Chromosome abnormality; Clinical; Clinical Data; Clinical Management; Clinical Trials; Collaborations; DNA; DNA Sequence Alteration; DNA sequencing; Deletion Mutation; Detection; Development; Diagnosis; Diagnostic; Enrollment; FDA approved; Focused Ultrasound; Gene Mutation; Glioblastoma; Glioma; Human; Institutional Review Boards; Lead; Lesion; Location; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Mediating; Microbubbles; Modeling; Molecular; Molecular Diagnosis; Molecular Profiling; Monitor; Neoplasms; Nerve Degeneration; Neuraxis; Non-Invasive Cancer Detection; Patients; Rattus; Recording of previous events; Research; Resistance; Rodent; Safety; Scientist; Solid Neoplasm; Specimen; Stream; Techniques; Technology; Testing; Ultrasonic Therapy; Ultrasonography; Work; anticancer research; brain tissue; clinical implementation; clinical translation; cranium; human disease; human model; image guided; improved; injured; liquid biopsy; pre-clinical; public health relevance; tumor; tumor DNA

Project Summary Molecular fingerprinting of chromosomal deletions and DNA mutations is increasingly important in the clinical management of patients with glioblastoma (GBM) – the most common and deadly primary adult brain tumor. While clinical analyses of tumor DNA have to this point relied on neurosurgical specimens, non-invasive detection through liquid biopsy of circulating tumor DNA (ctDNA) has the potential to revolutionize the detection and monitoring of these aggressive, heterogeneous, and treatment resistant neoplasms. Although several groups have detected ctDNA in patients with non-central nervous system (CNS) tumors, the protected location of brain tumors within the CNS likely limits the passage of molecules like ctDNA through the blood brain barrier (BBB). A new non-invasive technology to disrupt the BBB is magnetic resonance imaging-guided focused ultrasound (MRgFUS). MRgFUS can safely deliver ultrasound energy across the intact skull with high precision and accuracy, and is FDA-approved for the treatment of certain neurodegenerative conditions using high energy thermal lesioning. MRgFUS-mediated BBB disruption is accomplished with relatively low energy settings which are used to oscillate circulating microbubbles, perturbing and temporarily disrupting the BBB. The project team is leading the US clinical trials investigating MRgFUS-mediated BBB disruption in brain cancer patients, and have been pioneers in the sensitive and specific detection of ctDNA in the setting of solid tumors. Accordingly, we propose investigating MRgFUS to enable liquid biopsy of brain cancer through extra-CNS release of tumor DNA. Our overall hypothesis is that BBB disruption localized to specific brain tumor regions using MRgFUS will release tumor region-specific DNA into the circulation and this ctDNA will be detectable using our highly sensitive DNA sequencing technology. We further predict that the ultrasound settings can be further tuned and optimized to maintain safety and increase release of ctDNA to improve detection/diagnostic yield. We will test this hypothesis in two specific aims: In Aim 1, we will investigate the dynamics of FUS-triggered release of glioma DNA into the blood stream in advanced, faithful pre-clinical GBM rat models and determine the optimal settings and timing of tumor DNA release while maintaining safety. In Aim 2, we propose to assess the presence of tumor-specific DNA in the blood of brain tumor patients who will be already enrolled in MRgFUS-mediated BBBD clinical trials lead by our team. Successful completion of the work with establish the potential for MRgFUS enabled, non-invasive biopsy of GBM, which would radically advance the diagnosis and monitoring of human brain cancer.

项目概要 染色体缺失和 DNA 突变的分子指纹分析在临床中越来越重要 胶质母细胞瘤（GBM）患者的治疗——最常见和致命的原发性成人脑肿瘤。 虽然目前肿瘤 DNA 的临床分析必须依赖于神经外科标本，但非侵入性方法 通过液体活检对循环肿瘤 DNA (ctDNA) 进行检测有可能彻底改变检测方法 以及对这些侵袭性、异质性和治疗耐药性肿瘤的监测。 研究小组在非中枢神经系统 (CNS) 肿瘤患者中检测到了 ctDNA，这是受保护的部位 中枢神经系统内的脑肿瘤可能会限制 ctDNA 等分子通过血脑屏障的通道 (BBB) 是一种以磁共振成像引导为重点的破坏 BBB 的新型非侵入性技术。 超声波 (MRgFUS) 可以高精度地在完整的颅骨上安全地传递超声波能量。 和准确性，并经 FDA 批准用于使用高能量治疗某些神经退行性疾病 MRgFUS 介导的 BBB 破坏是在相对较低的能量设置下完成的。 用于振荡循环微泡，扰乱并暂时扰乱 BBB 项目团队。 正在领导美国临床试验，调查脑癌患者中 MRgFUS 介导的 BBB 破坏，以及 是实体瘤中 ctDNA 灵敏和特异性检测的先驱。 我们建议研究 MRgFUS，通过中枢神经系统外肿瘤释放来实现脑癌液体活检 我们的总体假设是，使用 MRgFUS 会破坏特定脑肿瘤区域的 BBB。 将肿瘤区域特异性 DNA 释放到循环中，并且可以使用我们的高灵敏度检测该 ctDNA 我们进一步预测超声波设置可以进一步调整和优化。 为了保持安全性并增加 ctDNA 的释放，以提高检测/诊断率，我们将对此进行测试。 假设有两个具体目标：在目标 1 中，我们将研究 FUS 触发的神经胶质瘤释放的动态 将 DNA 注入先进、忠实的临床前 GBM 大鼠模型的血流中，并确定最佳设置 在目标 2 中，我们建议评估肿瘤 DNA 释放的时间。 已入组 MRgFUS 介导的 BBBD 的脑肿瘤患者血液中的肿瘤特异性 DNA 我们团队领导的临床试验成功完成，确立了 MRgFUS 的潜力。 GBM 的非侵入性活检，这将从根本上推进人类的诊断和监测 脑癌。