Deploying Histotripsy Based Tumor Ablation Strategies to Treat Pancreatic Cancer

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PROJECT SUMMARY: Pancreatic cancer accounts for approximately 3% of all cancers in the United States and approximately 7% of all cancer related deaths. New treatment paradigms are direly needed. Emerging tumor ablation techniques have shown significant promise in both clinical and pre-clinical cancer studies. This proposal will focus on histotripsy, which is the first non-invasive, non-ionizing, non-thermal, image-guided tumor ablation modality that destroys tumors through the precise control of acoustic cavitation and is capable of overcoming many of the limitations of the other tumor ablation modalities currently under development for this malignancy. Recently, our research team completed proof-of-concept studies demonstrating that histotripsy is effective at targeting the pancreas and produces consistent, fast, and complete ablations, even in proximity to critical structures. Intriguingly, work by our team and others has also shown that histotripsy is effective in inducing systemic anti-tumor responses, resulting in post-treatment tumor regression both locally and at metastatic sites. However, the exact mechanism and level of control of this phenomenon is still unclear. The objective of this proposal is to utilize our pre-clinical mouse and novel pig animal models to expand upon the preliminary data presented in this proposal to generate critical mechanistic, safety, and efficacy data necessary to support future clinical trials in pancreatic cancer patients. Our overarching hypothesis is that histotripsy can achieve safe and selective focal ablation of pancreatic tumors and improve systemic anti-tumor immune responses. SPECIFIC AIM 1: Determine histotripsy treatment parameters for precise and complete pancreatic tumor ablation. Our preliminary data demonstrates the general feasibility of histotripsy ablation in the pancreas. This Aim will test the hypothesis that histotripsy can achieve precise, efficient, and complete ablation of pancreatic tumors without injuring critical structures, such as major blood vessels, bile ducts, and intestines. SPECIFIC AIM 2: Establish histotripsy treatment strategies for pancreatic cancer that optimize tumor ablation and systemic anti-tumor immune responses. This Aim will test the hypothesis that histotripsy is an effective treatment modality for precise and complete pancreatic tumor ablation in vivo. We also postulate that due to the unique features of histotripsy, focal tumor ablation results in predictable and tunable systemic anti-tumor host immune responses reducing metastatic burden and preventing recurrence. SPECIFIC AIM 3: Define histotripsy treatment parameters and determine its safety profile utilizing physiologically and clinically relevant porcine models of pancreatic cancer. Pigs better mimic human patients in terms of anatomy, size, and instrument scale. This Aim will test the hypothesis that histotripsy parameters can be established to effectively ablate orthotopic pancreatic tumors under physiologically and clinically relevant in situ conditions. SIGNIFICANCE: The studies outlined in this proposal will demonstrate the safety and efficacy of histotripsy for pancreatic cancer ablation and will provide critical data necessary for clinical translation to human patients.