Non-invasive Transcranial Histotripsy Treatment in a Murine Primary Malignant Brain Tumor Model

小鼠原发性恶性脑肿瘤模型的非侵入性经颅组织解剖治疗

• 批准号: 10225167
• 负责人: Aditya S Pandey
• 金额: $ 38.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225167
• 关键词: Ablation; Abscopal effect; Acoustics; Acute; Aftercare; Animals; Blood; Brain; Brain Injuries; Brain Neoplasms; Brain region; Caliber; Cancer Model; Cerebrum; Cessation of life; Clinical; Clinical Trials; Craniotomy; Data; Diagnosis; Disease; Edema; Effectiveness; Essential Tremor; Excision; FDA approved; Family suidae; Focused Ultrasound; Future; Glioma; Goals; Heating; Histology; Human; Immunization; Immunocompetent; Injury; Intervention; Lead; Length; Location; Magnetic Resonance; Magnetic Resonance Imaging; Malignant neoplasm of brain; Malignant neoplasm of liver; Mechanics; Metastatic Neoplasm to the Liver; Metastatic malignant neoplasm to brain; Methods; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Necrosis; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase; Physiologic pulse; Positioning Attribute; Preclinical Testing; Primary Brain Neoplasms; Radiation Dose Unit; Radiation necrosis; Radiation therapy; Rodent; Safety; Scanning; Secondary to; Sonication; Surface; System; Temperature; Time; Tissues; Trauma; Treatment outcome; Tumor Volume; Ultrasonic Therapy; Ultrasonography; animal data; base; brain tissue; clinical translation; clinically relevant; cranium; effective therapy; image guided; in vivo; millimeter; mortality risk; mouse model; non-invasive imaging; novel; pre-clinical; prevent; safety and feasibility; tumor

Title: Non-invasive Transcranial Histotripsy Treatment in a Murine Primary Malignant Brain Tumor Model Abstract The goal of this proposal is to investigate whether transcranial histotripsy treatment of brain tumors can lead to survival benefit in a murine primary malignant brain tumor model. Approximately 256,000 new patients are diagnosed with primary brain tumors annually worldwide, and many more patients have brain metastases. The first-option treatment is craniotomy-based surgical resection, a highly invasive surgery associated with high morbidities. Radiation therapy and drug-based therapy have shown limited effectiveness in treatment of brain tumors. There is a clear unmet clinical need for a noninvasive, safe, and effective treatment for brain tumors. Histotripsy is a non-invasive, image-guided ultrasound therapy based on acoustic cavitation. Guided by MRI and using microsecond ultrasound pulses delivered from outside the skull and focused inside the brain, transcranial histotripsy generates focal cavitation to mechanically liquefy the target brain tumor into acellular debris with millimeter accuracy. Transcranial histotripsy can be used to treat both primary brain tumors and brain metastases. Our group has constructed a human-scale transcranial MR guided histotripsy (tcMRgHt) system and demonstrated its safety and feasibility of non-invasive brain ablation in an in vivo large animal normal brain through an excised human skull. Unlike transcranial MR guided focused ultrasound (tcMRgFUS) that has limitations in treatment volume and location in the brain, tcMRgHt can be used to treat a wide range of volumes and locations in the brain by avoiding skull heating. To advance histotripsy towards clinical translation for treatment of brain tumors, a key question needs to be answered: Can transcranial histotripsy result in survival benefit in a clinically relevant brain tumor model? We have achieved very early and promising preliminary data suggesting that transcranial histotripsy can lengthen survival in a primary malignant brain tumor model – murine glioma GL261 model. The GL261 model has been widely used in preclinical testing of brain tumor treatment, however, very few treatment modalities have shown survival benefit in this mode due to its highly aggressive nature. In this R21, we propose to study the following two specific Aims in the murine GL261 model. Aim 1: Investigate the transcranial histotripsy parameters that can maximize the tumor kill while minimizing brain injury. Aim 2: Determine whether histotripsy can achieve survival benefit compared to the untreated controls. The data yielded here will reveal whether transcranial histotripsy can result in survival benefit in a preclinical primary malignant brain tumor model. The results are critical to determining the clinical feasibility of tcMRgHt as an effective, non-invasive treatment of malignant brain tumors and will be combined with our large animal data for FDA submission to start a future clinical trial.

标题：无创性经颅组织学治疗小鼠原发恶性脑瘤模型 摘要 这项提议的目的是调查经颅组织镜治疗脑肿瘤是否可以 在小鼠原发恶性脑瘤模型中导致生存受益。大约256,000个新的 全世界每年都有患者被诊断出患有原发性脑肿瘤，而且更多的患者患有脑肿瘤。 转移瘤。首选的治疗方法是基于开颅手术的手术切除，这是一种高度侵入性的手术。 与高发病率相关的。放射疗法和基于药物的疗法在以下方面的效果有限 脑瘤的治疗。临床上对非侵入性、安全和有效的治疗的需求显然没有得到满足。 治疗脑瘤。组织摩擦学是一种基于声学的非侵入性、图像引导的超声治疗方法。 空化。在MRI的引导下，使用从颅骨外发射的微秒超声脉冲和 聚焦于大脑内部的经颅组织探查术产生局部空化，以机械方式液化靶点。 脑瘤以毫米级精度变成无细胞碎片。经颅组织探查可用于治疗这两种疾病 原发脑瘤和脑转移瘤。我们的团队已经构建了一个人体尺度的经颅磁共振导引 组织学(TcMRgHt)系统，并论证了其无创性脑消融的安全性和可行性 活体大动物的正常大脑通过切除的人类头骨。不同于经颅MR引导聚焦 超声波(TcMRgFUS)在治疗体积和在脑中的位置有限制，可以使用tcMRgHt 通过避免头骨加热来治疗大脑中广泛的体积和位置。推进组织诊断学 对于脑肿瘤的临床翻译，需要回答一个关键问题：经颅能否 在临床相关的脑瘤模型中，组织摩擦学对生存有好处吗？我们很早就取得了成就， 有希望的初步数据表明，经颅组织碎石术可以延长原发恶性肿瘤的生存期 脑瘤模型-小鼠脑胶质瘤GL261模型。GL261模型已被广泛应用于临床前试验 然而，在脑肿瘤治疗中，很少有治疗方式在这种模式下显示出生存益处。 它的攻击性很强。在R21中，我们建议在小鼠身上研究以下两个特定目标 GL261型。目的1：探讨能使肿瘤杀伤率最大化的经颅组织学参数。 将脑损伤降至最低。目的2：确定组织摩擦是否可以获得生存益处。 未经处理的对照组。这里产生的数据将揭示经颅组织探查是否能带来生存益处。 在临床前的原发恶性脑瘤模型中。这一结果对确定临床可行性至关重要。 TcMRgHt作为一种有效的、非侵入性的治疗恶性脑肿瘤的方法，将与我们的 为FDA提交的动物数据，以开始未来的临床试验。

项目成果

Transcranial MR-Guided Histotripsy System.

• DOI: 10.1109/tuffc.2021.3068113
• 发表时间: 2021-09
• 期刊: IEEE transactions on ultrasonics, ferroelectrics, and frequency control
• 作者: Lu N;Hall TL;Choi D;Gupta D;Daou BJ;Sukovich JR;Fox A;Gerhardson TI;Pandey AS;Noll DC;Xu Z
• 通讯作者: Xu Z