Hepatocellular carcinoma (HCC) is a critical public health issue in the United States and especially in Texas due to in part from a growing epidemic of non-alcoholic fatty liver disease (NAFLD). It is estimated that 30% of the population have NAFLD and these individuals are at increased risk to develop more serious conditions such as non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In the United States it is estimated that in 2017 that there were 27,000 liver cancer related deaths. In Texas, liver cancers accounted for approximately 5% of all cancer related deaths in 2018 and from 2011-2015 was the fourth leading cause of cancer related deaths in men and the seventh l...

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Hepatocellular carcinoma (HCC) is a critical public health issue in the United States and especially in Texas due to in part from a growing epidemic of non-alcoholic fatty liver disease (NAFLD). It is estimated that 30% of the population have NAFLD and these individuals are at increased risk to develop more serious conditions such as non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In the United States it is estimated that in 2017 that there were 27,000 liver cancer related deaths. In Texas, liver cancers accounted for approximately 5% of all cancer related deaths in 2018 and from 2011-2015 was the fourth leading cause of cancer related deaths in men and the seventh leading cause of cancer related death in women. Currently therapies for advanced HCC are limited with mean five-year survival rates around 25%. Hence there is an urgent unmet clinical need to identify new preventative and treatment strategies for HCC. Recently, our laboratory has shown that the Hippo signaling pathway, first identified as a growth and organ size control pathway in fruit flies, plays a key role in protecting the liver from liver disease and progression of liver disease to liver cancer. We have also identified candidate genes and pathways that cooperate with Hippo signaling to prevent liver diseases and liver cancer. In this proposal we will extend our previous findings in two important directions. First, we will test the idea that targeting Hippo signaling will enhance the efficacy of cooperating pathway inhibition in prevention and treatment of advanced HCC in a mouse preclinical model of HCC associated with chronic liver disease and injury. Second, we will validate additional candidate Hippo pathway interacting genes for their ability to promote HCC in mice. These studies will provide novel insights into how HCC initiates and progresses and provide new avenues for therapeutic intervention.

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