Small molecule inhibitors targeting oncogenic drivers of hepatocellular carcinoma

DESCRIPTION provided by applicant Hepatocellular carcinoma HCC is the most prevalent cancer in human population and will lead to over deaths in the United States this year alone However the molecular mechanisms driving hepatocellular carcinoma HCC growth and metastasis remain elusive and there is a huge unmet medical need to find new therapeutic targets We performed an unbiased genome wide RNA interference RNAi screen to identify factors that are necessary for the epigenetic silencing of a HCC tumor suppressor Hedgehog Interacting Protein HHIP The RNAi screen was based on the rationale that factors necessary for epigenetic silencing of HHIP in HCC cells could in principle promote HCC tumor growth The RNAi screen identified three new drivers of HCC B cell lymphoma BCL histone deacetylase HDAC and CDC like kinase CLK RNAi based knockdown of these genes significantly inhibited HCC cell growth in culture and in a mouse model of HCC tumorigenesis Remarkably we found that these three genes are overexpressed in patient derived samples of HCC Furthermore their overexpression correlates with liver fibrosis and microvascular invasion both of which are markers of poor prognosis For this Phase I project we have chosen to develop small molecule inhibitors of BCL because it is a novel therapeutic target currently not exploited for HCC Our hypothesis is that pharmacological inhibition of BCL will suppress the HCC malignant phenotype Aim experiments will use two existing but therapeutically limited small molecule inhibitors to demonstrate the utility of this new HCC epigenetic therapeutic strategy using appropriate in vitro and in vivo models The inhibitors will be tested for inhibition of HCC cell growth in soft agar assays a surrogate assay for mouse tumorigenesis Cell based assays will also determine whether BCL inhibitors modulate HCC cell HHIP expression and expression of other downstream effectors such as cyclin D p and PIM A BCL inhibitor with efficacy in a mouse model of lymphoma will be tested for efficacy in an orthotopic xenograft based mouse model of HCC tumorigenesis Concurrently in Aim we will utilize our medicinal chemistry capabilities to create a focused library of up to new candidate BCL small molecule inhibitors that retain the beneficial inhibitory pharmacophore features of two existing structurally distinct inhibitors but add or eliminate other chemical features to address their off target effects and pharmacokinetic structural liabilities Structural activity relationships for these new merged pharmacophore compounds will be assessed by inhibition of BCL SMRT binding and by their ability to block HCC cell growth in soft agar assays In Aim we will proceed to in vivo efficacy testing of the top five candidates in a BCL dependent mouse xenograft model of HCC A successful Phase I project will reveal new and effective HCC therapeutic strategies and provide novel BCL inhibitors for Phase II medicinal chemistry to optimize efficacy and drug like properties The long term project goal is to develop a novel epigenetic therapy to significantly improve treatment of HCC patients PUBLIC HEALTH RELEVANCE Hepatocellular carcinoma HCC is the most prevalent cancer in human population It is universally and rapidly fatal leading to over deaths every year in the United States alone We discovered that BCL is necessary for HCC cells to form tumors in vivo in mice The goal of this project is to identify novel BCL inhibitors to serve as leads fo development of new drugs to effectively treat HCC patients