Validation and Credentialing of Patient-Derived Xenograft Models of Hepatocellular Carcinoma Using Patient Level Data

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide and the fastest rising cause of cancer-related death in the US. The majority of patients with HCC present with unresectable disease at diagnosis and a life expectancy of less than 20 months. This dismal prognosis has motivated the development of an expanding repertoire of treatment regimens, including locoregional therapies (LRT) such as transarterial chemoembolization (TACE) and radioembolization, as well as systemic therapies, notably tyrosine kinase inhibitors and immune checkpoint inhibitors, both alone and in combination. Despite these advances, treatment responses remain variable with most patients progressing on standard-of-care therapies. This deficiency issues, in large part, from limitations of current preclinical models in (i) recapitulating the intertumoral heterogeneity that characterizes HCC and (ii) predicting patient response to therapeutics. While patient-derived tumor models have been demonstrated to more faithfully recapitulate the heterogeneity of human tumors, there has been limited validation of the translational relevance of these models with respect to their ability to provide translationally reliable information for the design, testing and/or outcome evaluation of novel or existing therapies. Indeed, the creation of new patient-derived models of HCC requires rigorous validation of the resulting tumors to confirm their fidelity to the cancer of interest and robust credentialing criteria to ascertain their biological relevance and reliability as surrogates of patient response. In preliminary studies we have: 1) generated orthotopic HCC PDXs (PDOX) in rats derived from patients with unresectable HCC, 2) curated a clinical database of these patients including clinical and histologic phenotypes and treatment course 3) demonstrated the ability to perform LRT in these rat HCC PDOXs 4) generated humanized immune systems (HIS) and humanized livers (HL) in immunocompromised rats. The proposed project will build on this work to establish and validate a novel rat HCC PDOX model that incorporates the features required to realize the potential of the growing armamentarium of treatment paradigms for patients with HCC. We hypothesize that patient-derived rat models of HCC incorporating humanized immune systems as well as humanized livers with chronic liver injury are reliable surrogates of phenotypes as well as treatment responses observed in patients and enable the testing of questions of clinical importance. To test this hypothesis the proposed project will pursue three aims: (1) to validate a rat HCC PDOX model as a reliable surrogate of responses to eLRT observed in patients; (2) to establish a HIS rat HCC PDOX model that recapitulates responses to combination eLRT and systemic therapies observed in patients and (3) to define a HL rat model that reproduces phenotypes of chronic liver injury observed in patients with chronic liver disease. . Project Number: 1R01CA309041-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Terence Gade | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $667,041 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CTH-B (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11279298