Development of induced glioblastoma by implantation of a human xenograft in Yucatan minipig as a large animal model

Khoshnevis, Mehrdad; Carozzo, Claude; Bonnefont-Rebeix, Catherine; Belluco, Sara; Leveneur, Olivia; Chuzel, Thomas; Pillet-Michelland, Elodie; Dreyfus, Matthieu; Roger, Thierry; Berger, F.; Ponce, Frédérique

doi:10.1016/j.jneumeth.2017.03.007

Cited by 29 publications

(45 citation statements)

References 48 publications

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“…In fact, the density of tumoral tissue is higher than healthy tissue and can potentially increase the risk of suspension backflow after intratumoral injections [27]. So, further tests using a pig xenograft model of brain cancer will be necessary 1) to get some insight about the reflux issue and 2) to circumvent it inside the tumor by adjusting needle's gauge, flow rate and injection pressure [28].…”

Section: Stereotactic Injection In the Brain Of A Minipigmentioning

confidence: 99%

Synthesis of Highly-loaded Holmium-165 Siloxane Particles for Brachytherapy of Brain Cancer and Injectability Evaluation in Healthy Pig

Marcon¹,

Géhan²,

Khoshnevis³

et al. 2017

J Nanomed Nanotechnol

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Section: Stereotactic Injection In the Brain Of A Minipigmentioning

confidence: 99%

Synthesis of Highly-loaded Holmium-165 Siloxane Particles for Brachytherapy of Brain Cancer and Injectability Evaluation in Healthy Pig

Marcon¹,

Géhan²,

Khoshnevis³

et al. 2017

J Nanomed Nanotechnol

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“…In optimizing a model system for high-grade glioma, the use of a large animal system would provide improved utility for translation of neurosurgical strategies, device development, drug delivery, and radiologic study [24][25][26] . From an anatomic standpoint, the rodent brain is lissencephalic creating a minimization of drug leakage and improvement of local drug delivery 27,28 . Furthermore, the murine brain and spinal cord have significant developmental differences in comparison to large animal systems [27][28][29] .…”

mentioning

confidence: 99%

“…From an anatomic standpoint, the rodent brain is lissencephalic creating a minimization of drug leakage and improvement of local drug delivery 27,28 . Furthermore, the murine brain and spinal cord have significant developmental differences in comparison to large animal systems [27][28][29] . In addition to these anatomic considerations, the aforementioned concerns with immunocompromised models using xenograft cell lines have generated a translational space that may explain some of the limited success with preclinical strategies 4,25,30 .…”

mentioning

confidence: 99%

“…The genetic profile, immune system, and the size and anatomy of the porcine brain and spinal cord is recognized to better model the human 25,29,31 . For these reasons, device implantation, stereotactic radiosurgery, and intrathecal and intraparenchymal drug delivery have all been performed in pigs 7,27,[32][33][34][35][36] . Furthermore, while the Food and Drug Administration (FDA) has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for clinical relevance.…”

mentioning

confidence: 99%

“…Furthermore, while the Food and Drug Administration (FDA) has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for clinical relevance. Recognizing these considerations, groups have utilized the U87 xenografts in pigs, but required Cyclosporine-based immunosuppression and continued to face the known limitations of the U87 cell line 27,37 . Overall, existing animal models have limited translational utility due to a confluence of factors including immunogenicity, immunocompromised systems, variable recapitulation of histopathologic features, and limited anatomic translatability, highlighting the significance of generation and validation of an immunocompetent large-animal model.…”

mentioning

confidence: 99%

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Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs

Tora

Texakalidis

Neill

et al. 2020

Sci Rep

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Background: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer. Methods: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range. Results: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals. Conclusions: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs. High-grade glioma has a clinical picture of untenable morbidity and mortality 1,2. Given this clinical need, the U.S. National Library of Medicine has over 350 completed phase II-III clinical trials registered as of this writing. Unfortunately, there have been limited changes to the clinical outcomes in patients with high-grade glioma over the past years. In part, this represents the malignant nature of a disease that is refractory to a variety of treatment approaches. On the other hand, this raises the question of the translational value of existing pre-clinical animal models as a pathway to the clinic 3,4. Given numerous strategies with measured preclinical optimism including immunotherapy, oncolytic vectors, and targeted drug delivery, more appropriate large animal model systems are necessary to bridge the translational gap 5-10. In patients, high-grade gliomas present with marked invasion along white matter tracts and surrounding parenchyma, an immunosuppressive microenvironment, and significant inter and intra-tumoral heterogeneity 11. Existing models of high-grade gliomas are variable in recapitulation of these features. The most common are xenograft and syngeneic models which have drawbacks including non-invasive growth (9L, U87, U251), immunogenicity (U251, U87, C6, 9L), and restriction to murine (CT-2A, ...

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Development of Swine Models for Cancer Research: SCID Pigs and Other Emerging Pig Cancer Models

Boettcher¹,

Tuggle²

2022

Animal Models for the Development of Cancer Immunotherapy

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Development of induced glioblastoma by implantation of a human xenograft in Yucatan minipig as a large animal model

Cited by 29 publications

References 48 publications

Synthesis of Highly-loaded Holmium-165 Siloxane Particles for Brachytherapy of Brain Cancer and Injectability Evaluation in Healthy Pig

Synthesis of Highly-loaded Holmium-165 Siloxane Particles for Brachytherapy of Brain Cancer and Injectability Evaluation in Healthy Pig

Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs

Development of Swine Models for Cancer Research: SCID Pigs and Other Emerging Pig Cancer Models

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