Saturday, August 13, 2022
8/13/2022
PROJECT SUMMARY Hepatocellular carcinoma (HCC) accounts for nearly 31,000 deaths annually in the United States alone. Factors that epigenetically silence an HCC tumor suppressor gene have the potential to promote tumorigenesis and thus may provide novel drug targets for HCC therapies. Using a genome-scale shRNA screen, we identified BCL6 as a putative and novel HCC driver gene. BCL6 is a transcriptional repressor with no previously documented role in HCC development and progression. We found that BCL6 was sufficient to transform cultured immortalized hepatocytes and promote HCC tumor growth in mouse subcutaneous xenografts. These oncogenic effects of BCL6 were dependent upon the ability of BCL6 to cause transcriptional repression because a transcriptional repression activity defective mutant of BCL6 failed to transform hepatocytes and promote tumor growth in mice. Based on our preliminary results, in this application we will establish the role of BCL6 as a driver of HCC, determine the mechanism by which BCL6 promotes tumor growth, and evaluate novel BCL6 targeting small-molecule inhibitors for HCC therapy. In Aim 1, we will establish the role of BCL6 in initiation and progression of hepatic tumorigenesis using a series of complementary mouse models that recapitulate characteristic features of HCC, including a mouse model of liver fibrosis (cirrhosis). This model recapitulates cirrhosis which is a cardinal feature of HCC. Additionally, based on our preliminary results that BCL6 inhibition in HCC cells increases their probability of getting cleared by T-cells, we will also use a mouse model with humanized immune system to study the impact of BCL6 in HCC progression in the context of a functional human immune system. In Aim 2, based upon the results of our RNA-seq and further follow up analysis, we will determine if epigenetic silencing of tumor suppressor HHIP and the zinc transporter ZIP14 by BCL6 is necessary for it to drive hepatic tumor growth. In Aim 3, we will evaluate our novel BCL6 inhibitors in pre-clinical mouse models of HCC, including HCC patient-derived xenograft (PDX) models for HCC therapeutics. In preliminary experiments, we have developed a novel small-molecule inhibitor designed to target the BTB domain of BCL6 and thereby disrupt its interaction with its co-repressors SMRT, NCOR and BCOR. We found that this novel BCL6 inhibitor L2-12019 inhibited the HCC cell growth in culture and in a human HCC xenograft-based mouse model. In Aim 3 studies, we will rationally design and evaluate new L2-12019 analogs to improve drug-like properties. The lead analog (with improved potency, selectivity, stability and solubility) will be tested with L2-12019 in pre-clinical mouse models of HCC and its efficacy will be compared with existing BCL6 inhibitors. Collectively, the results of the experiments proposed in this application will elucidate a novel non-genetic druggable pathway that promotes HCC tumor growth and progression and evaluate a new approach for treating HCC.
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