Hepatocellular carcinoma (HCC) is the most common primary liver cancer. At diagnosis many patient tumors already are in an advanced stage for which no curative options exist. The current therapies such as sorafenib or anti-VEGF treatment (alone or in combination treatment) only extend the bad prognosis for these patients with a few months of average overall survival and induce severe side effects. New therapy options extending the life expectancy and the life quality of patients with advanced HCC are an urgent clinical need.

We here investigate in preclinical HCC models the impact of inhibiting the deubiquitinase UCHL1. This enzyme is part of a cellular system that controls the activity and stability of many key oncoproteins and as such affects cell division, DNA repair, protein homeostasis and controlled cell death. UCHL1 is considered an important target in different cancers. In HCC, it is strongly upregulated and correlated with poor patient survival.

We have shown in vitro that UCHL1 inhibition and the multiple tyrosine kinase inhibitor sorafenib reinforce each other to generate a strong cytotoxic effect on HCC cells at low doses. This proof of concept is the start of the current validation project. A number of combination treatments in which an UCHL1 targeting agent is combined with the FDA approved sorafenib or anti-VEGF treatments will be selected for validation in HCC mouse models: initially in a model in which the HCC tumor is chemically induced and subsequently in PDX-models of HCC (that use patient tumor material implanted in the mouse liver). With this strategy we aim to provide a strong rationale for initiating a clinical trial using UCHL1 inhibition in a combination treatment at the end of the project. In addition, patient HCC tumor cells will be ex vivo cultured and treated with a set of combination and monotreatments (including UCHL1 inhibition) in a 3D-test model. This approach aims to establish correlations between treatment response in vitro, patient tumor features and response to therapy in the clinic for a substantial patient cohort. This will set a knowledge base for possible future use of the 3D assay on patient tumors cells as a prognostic tool within the context of personalized medicine.

With this double approach of in vivo validation of UCHL1-combination treatments in function of starting clinical trial(s) and establishing treatment response in HCC models on a patient per patient basis, we aim to contribute to new therapy options or improved prognosis for patients with advanced HCC.