Patient Derived Xenografts Expand Human Primary Pancreatic Tumor Tissue Availability for ex vivo Irreversible Electroporation Testing

Rebecca M Brock,Melvin F Lorenzo,Robert C G Martin,Rafael V Davalos,Veronica M Ringel-Scaia,Navid Manuchehrabadi,Douglas J Grider,Natalie Beitel-White,Sheryl Coutermarsh-Ott,Irving C Allen

doi:10.3389/fonc.2020.00843

Abstract

New methods of tumor ablation have shown exciting efficacy in pre-clinical models but often demonstrate limited success in the clinic. Due to a lack of quality or quantity in primary malignant tissue specimens, therapeutic development and optimization studies are typically conducted on healthy tissue or cell-line derived rodent tumors that don't allow for high resolution modeling of mechanical, chemical, and biological properties. These surrogates do not accurately recapitulate many critical components of the tumor microenvironment that can impact in situ treatment success. Here, we propose utilizing patient-derived xenograft (PDX) models to propagate clinically relevant tumor specimens for the optimization and development of novel tumor ablation modalities. Specimens from three individual pancreatic ductal adenocarcinoma (PDAC) patients were utilized to generate PDX models. This process generated 15–18 tumors that were allowed to expand to 1.5 cm in diameter over the course of 50–70 days. The PDX tumors were morphologically and pathologically identical to primary tumor tissue. Likewise, the PDX tumors were also found to be physiologically superior to other in vitro and ex vivo models based on immortalized cell lines. We utilized the PDX tumors to refine and optimize irreversible electroporation (IRE) treatment parameters. IRE, a novel, non-thermal tumor ablation modality, is being evaluated in a diverse range of cancer clinical trials including pancreatic cancer. The PDX tumors were compared against either Pan02 mouse derived tumors or resected tissue from human PDAC patients. The PDX tumors demonstrated similar changes in electrical conductivity and Joule heating following IRE treatment. Computational modeling revealed a high similarity in the predicted ablation size of the PDX tumors that closely correlate with the data generated with the primary human pancreatic tumor tissue. Gene expression analysis revealed that IRE treatment resulted in an increase in biological pathway signaling associated with interferon gamma signaling, necrosis and mitochondria dysfunction, suggesting potential co-therapy targets. Together, these findings highlight the utility of the PDX system in tumor ablation modeling for IRE and increasing clinical application efficacy. It is also feasible that the use of PDX models will significantly benefit other ablation modality testing beyond IRE.

Highlights

While prevention and early diagnosis are key to reducing cancerrelated mortality, lack of treatments for many types of cancers, such as pancreatic cancer, has led to a stagnation in patient survival rates
To evaluate the potential of the patient-derived xenograft (PDX) model to function as a surrogate for human ex vivo pancreatic cancer tissue in tumor ablation modality studies, we utilized xenografts from three separate human patients (Table 1)
The lack of high-quality and low-quantity patient tissue for robust modeling has impacted the field. Other methods, such as cell lines, are useful for understanding basic mechanistic insight related to cancer biology and mechanisms of tumor ablation

Summary

Introduction

While prevention and early diagnosis are key to reducing cancerrelated mortality, lack of treatments for many types of cancers, such as pancreatic cancer, has led to a stagnation in patient survival rates. Current progress in ablation modalities has shown success in clinical trials by improving patient morbidity and mortality, crossing barriers impassable for surgery and chemotherapy. The treatment parameters for these ablation modalities often derive from modeling data generated from in vitro or ex vivo studies using the mechanical or electrical properties of healthy tissue or cell line data from rodents. Tumor tissue integrity declines over time once excised, leading to degradation of tissue mechanical and electrical properties that influence the accuracy of the in vitro and ex vivo modeling results compared to clinical application [2]

Methods

Results

Conclusion