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

基本信息

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
项目类别：
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

项目摘要

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：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抽象的该提案的目的是研究经颅组织解剖治疗脑肿瘤是否可以在小鼠原发性恶性脑肿瘤模型中导致约 256,000 个新的生存获益。全世界每年都会有患者被诊断出患有原发性脑肿瘤，而且还有更多的患者患有脑肿瘤首选治疗方法是开颅手术切除，这是一种高侵入性手术。与高发病率相关的放射治疗和药物治疗已显示出有限的效果。脑肿瘤的治疗对于无创、安全、有效的治疗有明显的未满足的临床需求。组织解剖学是一种基于声学的非侵入性图像引导超声治疗。由 MRI 引导并使用从颅骨外部传递的微秒超声脉冲和经颅组织切片术聚焦于大脑内部，产生局灶空化，以机械方式液化目标以毫米级精度将脑肿瘤转化为无细胞碎片可用于治疗这两种疾病。我们的团队构建了一个人体规模的经颅 MR 引导的脑肿瘤和脑转移瘤。组织解剖 (tcMRgHt) 系统，并证明了其在无创脑消融中的安全性和可行性与经颅 MR 引导聚焦的活体大型动物正常大脑不同。超声 (tcMRgFUS) 的治疗体积和大脑位置有限制，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。脑肿瘤临床转化治疗，需要回答一个关键问题：能否经颅我们很早就取得了临床相关脑肿瘤模型的组织解剖学成果？有希望的初步数据表明，经颅组织解剖可以延长原发性恶性肿瘤的生存期脑肿瘤模型——鼠神经胶质瘤GL261模型 GL261模型已广泛应用于临床前测试。然而，由于脑肿瘤治疗的局限性，很少有治疗方式在这种模式下显示出生存获益鉴于其高度攻击性，我们建议在小鼠中研究以下两个特定目标。 GL261模型。目标1：研究可以最大限度地杀死肿瘤的经颅组织切片参数。目标 2：确定组织解剖学与传统手术相比是否能够实现生存获益。此处产生的数据将揭示经颅组织切片术是否可以带来生存获益。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 作为一种有效的、非侵入性的恶性脑肿瘤治疗方法，并将与我们的大型研究相结合向 FDA 提交动物数据以启动未来的临床试验。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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