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.
