Developing Methods for Precise, Safe and Target-location Specific Histotripsy of Liver Tumors

PROJECT SUMMARY The goal of this grant is to optimize hepatic histotripsy to create safe and effective ablation in any location in a large animal, human-scale model. Liver cancer is a leading cause of death with ablation one of the limited curative options in select patients. Unfortunately, currently available ablation procedures have a variable local failure rate of ~10-40%. Also, tumors located near critical structures, such as bile ducts and bowel, often do not receive curative treatment as thermal ablation is associated with increased risk of injury. Histotripsy is the first non-invasive, non- thermal, and non-ionizing ablation modality, using focused ultrasound energy to create cavitation, resulting in mechanical tissue disruption. In preliminary studies, histotripsy has shown an ability to cause tissue disruption that spares certain structures with collagenous architecture, including bile ducts and bowel, and to create ablation zones with a thin margin between treated and normal tissues. To catalyze the clinical translation of histotripsy and potentially increase the number of patients eligible for curative treatment, a key question needs to be answered: Can we leverage the potential safety advantages of histotripsy while maintaining efficacy such that more tumors will be eligible for curative treatment? First, strategies to mitigate the effects of respiratory motion by decreasing liver motion with high-frequency jet ventilation or using in-suite cone-beam CT to model liver motion and modify prescriptions will be trialed in Aim 1. In Aim 2 we will determine dose thresholds to treat excised HCC while sparing critical structures to identify a safe, effective treatment dose for tumors of any location and then validate this dose in a survival, in vivo swine liver model. Finally, in Aim 3 we will advance a SCID-like HCC porcine liver tumor model, which will allow us to apply these strategies to tumors located within specific high-risk locations of the liver to confirm safety and efficacy, ultimately, proving our hypothesis that histotripsy can treat tumors in any liver location safely. The three Specific Aims are the following. Aim 1: Determine the best strategy to mitigate the effects of respiratory motion to increase the precision and safety of histotripsy ablation. Aim 2: To determine dose thresholds for liver cancer and critical structures ex vivo, allowing a trial of safe, effective treatment parameters for in vivo treatment in critical locations. Aim 3: Advance a highly relevant large animal liver HCC model for medical devices and confirm safety and efficacy in this large animal model. This project will yield critical preclinical data which will be necessary before the widespread adoption of histotripsy to treat patients with non-surgical hepatocellular carcinoma.