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

标题：小鼠原发性恶性脑肿瘤模型中的非侵入性经颅组织破坏治疗 摘要 这项建议的目的是调查是否经颅组织碎石术治疗脑肿瘤， 导致小鼠原发性恶性脑肿瘤模型中存活益处。约256，000新 全世界每年都有100多名患者被诊断患有原发性脑肿瘤， 转移首选的治疗方法是以开颅为基础的手术切除，这是一种高度侵入性的手术 与高发病率有关。放射治疗和药物治疗在以下方面显示出有限的效果： 脑肿瘤的治疗有一个明确的未满足的临床需要的无创，安全，有效的治疗 治疗脑瘤组织摧毁术是一种非侵入性的，图像引导的超声治疗， 气穴现象。在MRI引导下，使用从颅骨外输送的微秒级超声脉冲， 聚焦于大脑内部，经颅组织摧毁术产生局灶性空化，以机械方式覆盖目标 将脑肿瘤分解成无细胞碎片经颅组织碎石术可用于治疗 原发性脑肿瘤和脑转移瘤。我们的小组已经建立了一个人类规模的经颅磁共振引导 组织摧毁术（tcMRgHt）系统，并证明其安全性和可行性的非侵入性脑消融在一个 活体大动物正常大脑通过切除的人类头骨。与经颅磁共振引导聚焦不同， 超声（tcMRgFUS）在治疗体积和脑内位置方面有局限性，可以使用tcMRgHt 通过避免颅骨加热来治疗大脑中的大范围体积和位置。为了推进组织分解术 对于脑肿瘤治疗的临床转化，需要回答一个关键问题： 在临床相关脑肿瘤模型中，组织破坏导致存活益处？我们很早就实现了， 有希望的初步数据表明，经颅组织碎石术可以延长原发性恶性肿瘤的生存期， 脑肿瘤模型-鼠胶质瘤GL 261模型。GL 261模型已广泛用于临床前试验 然而，很少有治疗方式在这种模式下显示出生存益处， 它极具攻击性的本性在这个R21中，我们建议在小鼠中研究以下两个特定的目的。 GL 261型号。目的1：研究可以最大限度地杀死肿瘤，同时 最大限度地减少脑损伤目的2：确定组织破坏术是否可以实现生存益处， 未处理的对照。本研究的数据将揭示经颅组织碎石术是否能提高患者的生存率 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，非侵入性的治疗恶性脑肿瘤，并将结合我们的大型 提交给FDA的动物数据，以开始未来的临床试验。

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.