The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform

Abstract

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model—the Oncopig Cancer Model (OCM)—as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D, the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.

Improved, Shorter-Latency Carcinogen-Induced Hepatocellular Carcinoma Model in Pigs

“…A relevant porcine HCC model is that of the transgenic "oncopig" cancer model with Cre recombinase inducible TP53R167H and KRASG12D genes [40,41]. A primary hepatocyte cell line from an oncopig was exposed to a Cre-encoding adenovirus in vitro resulting in primary porcine HCC with similar histopathologic characteristics as human HCC [42].…”

KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

“…Given these advantages, several porcine models of cancer are emerging. These include a mutant APC porcine model of familial adenomatous polyposis (FAP), a heterozygous TP53 knockout model of spontaneous osteosarcomas, and a chemically induced hepatocellular carcinoma (HCC) model 32 . Similarly, our inducible LSL-KRAS G12D -TP53 R167H model has successfully generated soft tissue sarcomas and HCC 16,32,33 .…”

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“…The size and anatomy of the pig liver, which is similar to that of humans, allows for utilization of instruments and devices employed in the care of patients, enabling easier application and translation to human clinical trials. [42] Unlike other animal models, pigs also exhibit similar genetics and drug metabolism to humans, [43] which allows for relevant investigation of the molecular basis of disease in addition to drug pharmacokinetics and therapeutic analyses. Until recently, pigs were most commonly used for practicing techniques rather than modeling disease; however, the establishment of porcine HCC models shows great promise in advancing diagnostic and therapeutic discoveries for liver cancer.…”

“…Finally, the OCM is immunocompetent, lending itself to the investigation of immunotherapies. [42] Given these attributes, the OCM has potential to serve as a valuable transitional bridge between preclinical small animal murine studies and human clinical trials.…”