Optimization of High Frequency Irreversible Electroporation (H-FIRE) for tumor ablation and immune system activation in pancreatic cancer applications - 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. This proposal will focus on High-Frequency Irreversible Electroporation (H-FIRE), which delivers a series of electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane resulting in cancer cell death. The objective of this proposal is to utilize our mouse and novel pig preclinical animal models to expand upon the preliminary data presented in this proposal and generate critical mechanistic, safety, and efficacy data necessary to support future H-FIRE clinical trials in pancreatic cancer patients. Our overarching hypothesis is that H-FIRE will effectively mitigate heterogeneity in physiologically and clinically relevant pancreatic tumors, with treatments leading to contiguous zones of ablation near critical tissue structures. We further postulate that the benefits of H-FIRE will ultimately extend beyond focal tumor ablation and generate a predictable, tunable systemic anti-tumor immune response reducing metastatic burden and preventing recurrence. Specific Aim 1 will characterize the biophysical response of pancreatic cancer cells and tissues to H-FIRE. This Aim will evaluate the hypothesis that H-FIRE pulse parameters can be tuned to achieve different cell death outcomes (apoptosis, pyroptosis, necroptosis, or necrosis) that are highly relevant to tumor ablation, the tumor microenvironment, and anti-tumor immune responses. In concert, we will assess ablation development with real time treatment feedback using Fourier Analysis Spectroscopy (FAST). We expect to determine which parameters (i.e. pulse width, energized time, interphase/interpulse delay) play significant roles in tuning cell death elicited within relevant cancer cell lines and ex vivo tissues. Specific Aim 2 will establish H-FIRE treatment strategies for pancreatic cancer that optimize tumor ablation and systemic anti-tumor immune responses. Using Pan02 mouse models, this Aim will test the hypothesis that H-FIRE is an effective treatment modality for precise and complete pancreatic tumor ablation in vivo. We also postulate that due to the unique features of H-FIRE mediated cell death and resultant changes in the tumor microenvironment, focal tumor ablation will result in predictable and tunable systemic anti-tumor host immune responses reducing metastatic burden and preventing recurrence. Specific Aim 3 will define H-FIRE treatment parameters and determine its safety profile utilizing physiologically and clinically relevant porcine models of pancreatic cancer. This Aim will test the hypothesis that H-FIRE can effectively ablate orthotopic pancreatic tumors under physiologically and clinically relevant in situ conditions. To test this hypothesis, we will utilize novel, orthotopic, porcine pancreatic cancer models featuring a diverse range of clinically relevant physical properties that are predicted to impact H-FIRE efficacy in human patients.
