Hepatocellular carcinoma (HCC), or primary liver cancer, is a deadly malignancy that spans more than 780,000 new diagnoses and causes 750,000 annual deaths. Alcoholic liver disease represents a common chronic liver ailment that is progressive and incites liver cirrhosis?a precancerous state of liver scarring?that increases the risk for HCC development. While preclinical animal models represent pivotal tools to study liver cancer, current preclinical animal models for HCC and liver cirrhosis are significantly restricted by the lack of systems of similar size, physiology, genetic makeup, and drug metabolism compared to humans. We have recently developed the Oncopig Cancer Model (OCM), a unique transgenic pig model that develops inducible site and cell specific tumors after Cre recombinase exposure. Our initial investigations have demonstrated that OCM HCC recapitulates human HCC both histologically and genomically. We have also demonstrated the capability to develop METAVIR F2-F3 alcohol-induced liver fibrosis in the OCM, providing a unique opportunity to study HCC in its native cirrhotic liver background. The overarching goal of our research is to improve the survival of patients with HCC and liver cirrhosis by applying the OCM to investigate disease prevention, detection, treatment, and follow-up in a translational fashion. Given the critical importance of radiologic imaging in the diagnosis, therapeutic planning, and post-treatment follow-up of HCC and liver cirrhosis, this proposal is undertaken with the specific purpose of developing, adapting, optimizing, and pre- clinically validating a magnetic resonance imaging (MRI) and elastography (MRE) protocol for the detection, diagnosis, and characterization of HCC and quantification of liver cirrhosis using advanced non-invasive radiologic imaging. Our rationale is that the development and application of a minimally invasive, MRI/MRE liver imaging protocol tailored to the OCM platform can facilitate preclinical investigations aimed at the discovery and therapeutic response monitoring of HCC and liver disease in order to significantly improve prevention, detection, and survival of patients with this condition. Without enabling such technologies for preclinical investigation and clinical translation, pathways toward early detection, diagnosis, and treatment of liver cancer and cirrhosis are unlikely.
The Specific Aims of the proposed effort are as follows: (1) To configure, test, revise, and optimize an MRI/MRE liver imaging protocol for the detection, diagnosis, and characterization of HCC and quantification of liver cirrhosis in the OCM; (2) To validate our OCM liver MRI/MRI protocol via radiologic-pathologic correlation between imaging findings and liver tissue biopsy samples.
The Oncopig is a unique pig model that can be used to study alcoholic liver disease and liver cancer, both of which are prevalent diseases that result in considerable worldwide illness and fatality. The aim of this research study is to use the Oncopig to develop and validate an advanced magnetic resonance imaging exam aimed at improving the detection and characterization of liver disease and cancer in order to enable discoveries in animal studies which could then be translated to human trials. The work proposed in this grant could thus lead thus lead to important advances in the diagnosis and treatment of liver disease and cancer.