Abstract

Background:

Active HCV infection has decreased with the introduction of direct-acting antivirals (DAAs). However, a subset of patients remains at risk for HCC development even after achieving a sustained virologic response (SVR). Chemopreventive measures post SVR are urgently needed to reduce incident HCC.

Methods:

We first validated our previously reported Prognostic Liver Signature (PLS) for association with post-SVR HCC risk in two independent cohorts of HCC-naïve (n=41) and HCC-experienced (n=85) patients with longitudinal observation up to 20 years. Post-SVR HCC risk driver genes were determined using multiscale embedded gene co-expression network analysis and based on association with time to HCC development. Candidate compounds targeting the HCC risk driver genes were tested for PLS modulation in a PLS-inducible cell culture system (cPLS) and ex vivo culture of clinical precision-cut liver slice (PCLS) for PLS modulation. HCC-preventive effect of the compound was assessed in two mouse models of HCC development: fibrosis/HCC induced by DEN + CCl4 and NASH HCC induced by genetic knockout of Pten and Scap genes (Pten/Scap-ko).

Results:

PLS was associated with long-term post-SVR HCC incidence in the HCC-naïve (adjusted hazard ratios [aHR], 5.02; 95% CI, 1.26-19.9) and HCC-experienced (aHR, 2.28; 95% CI, 1.01-5.15) patient cohorts. Among the PLS member genes, 19 putative key HCC risk driver genes were identified, including DDR1 as the most strongly associated with time to HCC development in multiple independent clinical cohorts. A comprehensive computational compound screening suggested a small molecule DDR inhibitor as a top candidate for reversal of high-risk PLS. A clinically developed DDR1 inhibitor, 7rh, significantly reversed high-risk PLS in the in vitro cPLS system and ex vivo PCLS culture. Further, 7rh diminished HCC development in the DEN + CCl4 mouse model accompanied by reversal of the high-risk pattern of PLS, whereas this effect was not observed in the Pten/Scap-ko mouse model. No notable toxicity was observed.

Conclusion:

Our pre-clinical study suggests that 7rh is a candidate post-SVR HCC chemoprevention agent with PLS as a companion biomarker to guide its indication and monitor the effect.