Thursday, November 21, 2024
11/21/2024
Abstract Hepatocellular carcinoma (HCC) causes more than 600,000 deaths worldwide and 12,000 deaths in United States per year. The overall survival of patients with HCC is less than 18% and most patients with HCC have limited treatment options. There is an urgent need to develop new and more effective therapeutic strategies and agents to treat HCC. Over the years we have identified focal adhesion kinase (FAK) as a promising target to treat HCC. We found that FAK is amplified and overexpressed in 16% of HCC specimens. We found that deletion of Fak in hepatocytes suppressed c-Met (MET)/β-catenin (CAT)-induced HCC tumor growth and prolonged survival of animals. We demonstrated that FAK kinase activity is critical for HCC development and FAK kinase inhibitors effectively suppressed HCC tumor growth. We further discovered that overexpression of both FAK and CAT, but neither FAK nor CAT alone, in mouse livers was sufficient to lead to HCC formation through an increased expression of AR. Despite all these exciting findings, more studies are warranted in better understanding the molecular mechanisms by which FAK functions in liver cancers. The Overall Objective of this grant is to answer three questions: 1, how does FAK promote HCC growth? 2, can we target FAK to improve the efficacy of current target therapies? 3, as HCC cells acquire resistance to FAK inhibitors treatment, how can we overcome this resistance? In the proposal, Aim1 will examine how FAK overexpression promotes glycolysis. Aim 2 will investigate if targeting FAK will improve the efficacy of lenvatinib. Aim 3 will dissect the mechanisms by which HCC cells acquire resistance to FAK inhibition. The results from this study will provide an important mechanistic basis for therapeutic intervention to treat HCC by targeting FAK.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
