Title: Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma
Mark Feitelson, Ph.D., Department of Biology, Temple University, Philadelphia, PA 19122
Statement of the Problem: Hepatocellular carcinoma (HCC) is the 5th most prevalent tumor type and second leading cause of cancer related deaths worldwide. The most common etiologies associated with HCC are chronic infections with hepatitis B and C viruses. Although early HCC is curable by surgical resection, it is often asymptomatic and rarely diagnosed in time. There are many treatment modalities used for patients with advanced HCC, but the efficacy of each approach is limited. Sorafenib and other multi-kinase inhibitors have been approved for the treatment of advanced HCC, but these only extend life for up to a year. Alterations in the composition of gut bacteria have been documented in HCC. Since HCC arises on the background of chronic liver disease (CLD), experiments were carried out to test the hypothesis that the re-establishment of a normal gut microbiome would impact upon the pathogenesis of CLD and HCC. Methodology: To test this hypothesis, a transgenic mouse model that expressed the hepatitis B oncoprotein, HBx, was used. This model recapitulates most of the pathology and alterations in many molecular pathways that contribute to human HCC in 100% of the animals within 10-12 months. Results: When these mice were fed with selected probiotics for several weeks prior to the appearance of dysplastic nodules, half the mice had no evidence of dysplasia, and the rest had smaller nodules and/or small regions of dysplastic cells. Similar results were observed when mice were treated for several weeks before the appearance of HCC. More than half the animals had no evidence of HCC, and those with tumors had fewer and smaller nodules. Conclusions: These observations suggest that manipulation of the gut microbiome delay or block the pathogenesis of CLD and HCC.