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

项目摘要 染色体缺失和DNA突变的分子指纹图谱在临床上越来越重要 胶质母细胞瘤(GBM)是最常见和最致命的成人原发脑肿瘤。 虽然到目前为止，对肿瘤DNA的临床分析依赖于神经外科标本，但非侵入性 通过液体活检检测循环肿瘤dna(Ctdna)具有使检测发生革命性变化的潜力。 以及对这些侵袭性、异质性和治疗耐药肿瘤的监测。尽管有几个 研究小组在非中枢神经系统(CNS)肿瘤患者的保护位置检测到了ctDNA 中枢神经系统内的脑瘤可能会限制ctdna等分子通过血脑屏障。 (Bbb)。一种新的非侵入性破坏血脑屏障的技术是磁共振成像引导聚焦 超声(MRgFUS)。MRgFUS可以安全、高精度地将超声能量传递到完整的颅骨 和准确性，并被FDA批准用于治疗某些神经退行性疾病使用高能量 热力调节。MRgFUS介导的BBB中断是在相对较低的能量设置下完成的， 被用来振荡循环微泡，扰乱和暂时扰乱血脑屏障。项目团队 正在领导研究MRgFUS介导的脑癌患者血脑屏障中断的美国临床试验，以及 在实体瘤环境中敏感和特异地检测ctDNA方面一直是先驱。因此， 我们建议研究MRgFUS，通过肿瘤的中枢神经系统外释放，实现脑癌的液体活检 DNA我们的总体假设是，使用MRgFUS将血脑屏障干扰定位于特定的脑肿瘤区域 将肿瘤区域特异性DNA释放到循环中，这种ctDNA将被检测到使用我们高度敏感的 DNA测序技术。我们进一步预测，超声设置可以进一步调整和优化 保持安全性并增加ctDNA的释放，以提高检测/诊断效率。我们将对此进行测试 两个特定目标的假设：在目标1中，我们将研究FUS触发的胶质瘤释放的动力学。 将DNA注入先进的临床前GBM大鼠模型的血流中，并确定最佳设置 以及肿瘤DNA释放的时机，同时保持安全。在目标2中，我们建议评估是否存在 脑肿瘤患者血液中肿瘤特异性DNA的变化 由我们团队领导的临床试验。成功完成了与建立MRgFUS的潜力的工作 能够对基底膜进行非侵入性活组织检查，这将从根本上提高对人类 脑癌。

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.