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

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

doi:10.3389/fonc.2020.00843

Cited by 16 publications

(26 citation statements)

References 33 publications

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“…(Fig. 7 ) 24 . The PHPC tissue (n = 7), excised Panc01 tumor tissue (n = 7), and murine PDX tissue (n = 9) exhibited initial conductivities of 0.231 ± 0.058 S/m, 0.242 ± 0.043 S/m, and 0.225 ± 0.070 S/m, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the historic use of mice in IRE and other tumor ablation modality development 24 , 38 – 40 , we next compared the Panc01 tumors grown in this study from the RAG2/IL2RG pigs with Pan02 tumors generated in immunocompetent mice and PDX tissue derived tumor generated in immunocompromised mice. Previous studies have utilized human xenografts in immunocompromised mice or murine tumor injection into immunocompetent animals to generate tissue for ex vivo IRE studies.…”

Section: Resultsmentioning

confidence: 99%

“…General comparison of the porcine xenografted Panc01 tumors to the murine Pan02 tumors and PDAC murine xenografted PDX tumors, is based upon the latter two models’ well-established roll in studying cancer therapies 24 , 38 – 40 , 43 . Based on histology, the xenograft Panc01 tumors share comparable features of interest with the accepted PDX human-tumor xenografted models.…”

Section: Discussionmentioning

confidence: 99%

“…In an attempt to bridge this gap, more researchers are using patient-derived tumor xenograft (PDX) models for oncological studies. In these models, human tumors are engrafted into immunocompromised mice, allowing the local microenvironment of the human tumor to be recapitulated in the mouse 11 , 21 – 24 . While the PDX model is an impressive improvement to mouse models, the anatomical differences between mice and humans still presents a barrier to clinical relevance.…”

Section: Introductionmentioning

confidence: 99%

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Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation

Hendricks-Wenger

Aycock

Nagai-Singer

et al. 2021

Sci Rep

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New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation

Hendricks-Wenger

Aycock

Nagai-Singer

et al. 2021

Sci Rep

Self Cite

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“…However, a majority of these studies did not fully consider alternative cell death types. While apoptosis is certainly occurring in some cells within the treatment zone, our data suggest that treatment could initiate multiple types of cell death mechanisms, though the size and shape of the regions in which each type is experienced may vary between clinical treatments due to differences in pulsing parameters, tissue type, and treatment time [ Figure 2 ; ( 97 , 98 )]. This is mediated, in part, by the proximity of the cells to the electrodes, which impacts the voltage each cell experiences during treatment ( 28 , 99 – 101 ).…”

Section: Electroporation-based Ablation Modalitiesmentioning

confidence: 99%

Starting a Fire Without Flame: The Induction of Cell Death and Inflammation in Electroporation-Based Tumor Ablation Strategies

et al. 2020

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New therapeutic strategies and paradigms are direly needed for the treatment of cancer. While the surgical removal of tumors is favored in most cancer treatment plans, resection options are often limited based on tumor localization. Over the last two decades, multiple tumor ablation strategies have emerged as promising stand-alone or combination therapeutic options for patients. These strategies are often employed to treat tumors in areas where surgical resection is not possible or where chemotherapeutics have proven ineffective. The type of cell death induced by the ablation modality is a critical aspect of therapeutic success that can impact the efficacy of the treatment and systemic anti-tumor immune system responses. Electroporation-based ablation technologies include electrochemotherapy, irreversible electroporation, and other modalities that rely on pulsed electric fields to create pores in cell membranes. These pores can either be reversible or irreversible depending on the electric field parameters and can induce cell death either alone or in combination with a therapeutic agent. However, there have been many controversial findings among these technologies as to the cell death type initiated, from apoptosis to pyroptosis. As cell death mechanisms can impact treatment side effects and efficacy, we review the main types of cell death induced by electroporation-based treatments and summarize the impact of these mechanisms on treatment response. We also discuss potential reasons behind the variability of findings such as the similarities between cell death pathways, differences between cell-types, and the variation in electric field strength across the treatment area.

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Characterization of Miniature Probes for Cryosurgery, Thermal Ablation, and Irreversible Electroporation on Small Animals

Ranjbartehrani

Etheridge

Ramadhyani

et al. 2022

Advanced Therapeutics

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Focal therapies, including cryosurgery, thermal ablation, and irreversible electroporation (IRE) are widely used in the treatment of cancer and other diseases, aimed at exposing cancer cells to extreme physical conditions leading to cell death. Focal ablation outcomes are extensively studied in small animal preclinical models, such as mice; however, robust engineering characterization of these treatments is largely lacking, due in a large part to the lack of control in applying clinical devices (cm scale) to mouse tumors (mm scale). To address this issue, miniaturized probes are designed and built for controlled application of cryosurgery, thermal ablation, and IRE and their performance is evaluated using ex vivo porcine liver tissue and an in vivo MC‐38 tumor model. These experimental results are compared to simulated conditions in heat transfer (cryosurgery and thermal ablation) and electrical (IRE) models. Agreements of physical quantities between measurement and modeling are shown for all the focal therapy cases. The in vivo outcome is further correlated with tumor growth delay. The characterization improves the understanding of the energy dose to create tissue damage, therefore enables to better understand outcomes in preclinical studies and predict and optimize the outcome of future clinical procedures.

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

Cited by 16 publications

References 33 publications

Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation

Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation

Starting a Fire Without Flame: The Induction of Cell Death and Inflammation in Electroporation-Based Tumor Ablation Strategies

Characterization of Miniature Probes for Cryosurgery, Thermal Ablation, and Irreversible Electroporation on Small Animals

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