An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a global health burden ranking as the fourth most common and second deadliest cancer in the world. Effective therapeutic strategies for HCC, especially at advanced stages, are limited due to tumor heterogeneity, underlying patient comorbidities, and lack of identified biomarkers for disease

management. Overall survival rates for advanced disease are just 5-14%, indicating that improved therapies are needed. Historically, rodents have served as the predominant preclinical model, but results in these studies have not translated to successful human application. Limitations of these and other models include variations in the

genetic and molecular mechanisms of tumorigenesis, inconsistencies in immunity and tumor microenvironments, and marked differences in size, anatomy, and physiology. Shortcomings of these models create barriers to identifying targetable biomarkers, developing device and imaging technologies, pharmaceutical treatments, and

techniques for biopsy and surgery, all of which are necessary to improve outcomes for HCC patients. To create a platform whose preclinical testing will translate to innovation in these fields of HCC management, we have developed methods to induce HCC in the liver of minipigs using somatic cell gene editing. Our minipig platform

is ideal for therapeutic development as the size, physiology, anatomy, and metabolism of minipigs are closely related to humans. Moreover, liver function, segmental anatomy, biliary tree, and hepatic vasculature are markedly similar to humans. To date, we have proven the feasibility of this approach in developing solid liver

tumors rapidly and reproducibly with induced molecular changes identified in HCC patients. In this proposal, we aim to advance our HCC platform for use in precision medicine innovation by refining our HCC minipig models to recapitulate the molecular phenotype specific to the most common subtype of human HCC. We will conduct

a drug study with the standard of care systemic therapy, sorafenib, to determine if our swine model responds comparably to human patients. Achievement of these aims will help validate our novel minipig platform, and segway into future studies (1) evaluating the safety and efficacy of molecularly targeted therapies, drug delivery

devices, and tumor embolization, ablation, and cryotherapeutic technologies, (2) developing novel imaging methods, (3) studying processes of tumorigenesis, and (4) identifying biomarkers for early diagnosis and therapeutic strategies. The minipig HCC platform will bring innovative approaches to HCC, translating results

preclinical studies to improved patient outcomes in the clinic by bolstering clinical trial success rates in a cost- effective and time-efficient manner. In Phase II work, these models will be refined and developed in the context of relevant co-morbidities such as underlying liver disease and validated in clinical trial-like scenarios as proof of

concept for commercialization.