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

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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.