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：鼠主要恶性脑肿瘤模型中的非侵入性经颅组织疗法治疗 抽象的 该提议的目的是研究脑瘤的thrancranial Histotipsy治疗是否可以 导致鼠类原发性恶性脑肿瘤模型的生存益处。大约256,000个新的 患者每年在全球诊断出患有原发性脑肿瘤，更多的患者患有大脑 转移。第一选择治疗是基于颅骨术的手术切除，这是一种高度侵入性的手术 与高病态有关。放射疗法和基于药物的治疗在 对于非侵入性，安全和有效的治疗，明显未满足的临床需求 用于脑肿瘤。组织疗法是一种基于声学的非侵入性，图像引导的超声治疗 空化。由MRI指导并使用从头骨外部传递的微秒超声脉冲和 thrancranial Histotipsy聚焦在大脑内部，产生局灶性空化，以机械液化目标 脑肿瘤以毫米精度为细胞碎片。经颅组织疗法可用于治疗 原发性脑肿瘤和脑转移。我们的小组已经建立了人类规模的trancranial先生。 组织疗法（TCMRGHT）系统，并证明了其在IN中无创脑消融的安全性和可行性 体内大动物正常大脑通过令人兴奋的人类头骨。与thrancranial先生不同 超声（TCMRGFU）在治疗量和大脑中的位置有限制，可以使用TCMRGHT 通过避免颅骨加热来治疗大脑中的各种体积和位置。提高组织疗法 临床翻译以治疗脑肿瘤，需要回答一个关键问题：可以经颅是否 在临床上相关的脑肿瘤模型中，组织疗法会导致生存益处？我们已经很早就成就了 有希望的初步数据表明，thrancranial Histotipsy可以延长主要恶性肿瘤的生存率 脑瘤模型 - 鼠神经胶质瘤GL261模型。 GL261模型已广泛用于临床前测试 然而，在此模式下，很少有治疗方式显示出生存益处 具有高度侵略性的本质。在此R21中，我们建议在鼠中研究以下两个特定目标 GL261模型。 AIM 1：研究可以最大化肿瘤杀死的thrancranial Histotipsy参数 最小化脑损伤。 AIM 2：确定与组织疗法相比是否可以实现生存益处 未经处理的控件。这里产生的数据将揭示thrancranial Histotipsy是否会导致生存益处 在临床前原发性恶性脑肿瘤模型中。结果对于确定临床可行性至关重要 TCMRGHT是一种有效的，无创的恶性脑肿瘤治疗，将与我们的大型 FDA提交的动物数据开始了未来的临床试验。

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