Keynote: The Oncopig Cancer Model, an Innovative Large Animal Platform for Preclinical Evaluation of Novel Therapeutic Approaches

The global incidence of cancer is rapidly rising and remains a leading cause of death worldwide. While human clinical trials are the benchmark for testing cancer therapies, regulatory, enrollment, and financial challenges of trial inception are significant. Advances in cancer care are therefore dependent upon the use of preclinical model systems to test new treatments. However, current preclinical cancer models have disadvantages that limit effective translation of novel therapeutic approaches to clinical practice. A large number of rodent cancer models have been developed; however, differences in drug metabolism make rodents poor models of toxicity and efficacy in preclinical studies, of immense importance as <8% of drugs translate successfully from animal testing into clinical trials. The small size of rodents also prohibits the use of the same imaging approaches, devices, and techniques employed in clinical practice. As such, there is a significant need for a clinically relevant large animal cancer models for preclinical evaluation of novel therapeutic dosing, delivery, biodistribution, safety, and effectiveness. Pigs serve as a promising preclinical model for evaluation of novel image-guided and surgical therapeutic approaches given their similar size, anatomy, physiology, genetics, immunity, and metabolism compared to humans. This presentation will focus on the development, characterization, and utilization of the Oncopig Cancer Model® to address this unmet preclinical cancer modeling need. The Oncopig® is a transgenic inducible porcine cancer model that develops tumors in defined locations following Cre recombinase induced expression of KRASG12D and TP53R167H driver mutations. To date Oncopigs® have been used to model a range of tumor types including pancreatic, liver, kidney, color, bladder, and lung cancers. Oncopig® tumors consistently develop within two weeks, with sizes ranging from 0.5 up to 3 cm in size depending on the AdCre dose used and organ targeted. Tumors are monitored and targetable using clinically relevant imaging modalities (CT, MRI, ultrasound, fluoroscopy, endoscopy), making them ideal models for preclinical evaluation of novel surgical devices and image-guided therapies. To date the Oncopig® has successfully been utilized for preclinical evaluation of ablation devices, arterially directed therapies, and novel Y90 approaches. However, as with all animal models, the Oncopig® is not without limitations, which include lack of control of tumor histology due to non-specific AdCre cell targeting and spontaneous regression resulting from immune recognition and tumor cell killing. To address these limitations, new approaches to induce tumors through autologous and allograft Oncopig® cancer cell injection have been developed. Once optimized, these novel approaches will facilitate development of Oncopig® tumors with defined tumor histology suitable for long-term efficacy studies. Use of cancer cell lines for tumor induction also provides the opportunity to introduce defined driver mutational profiles and induce expression of therapeutic targets of interest for preclinical evaluation of precision medicine approaches. Current efforts to develop a Mini-Oncopig® model will further enable long term follow up and preclinical pharmaceutical evaluations. Together, this work demonstrates the relevance and future potential of the Oncopig® model for physician training and preclinical evaluation of novel surgical, image-guided, and targeted therapeutic approaches prior to translation into clinical practice.