Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for over 30,000 deaths each year in the United States alone. Regrettably, current therapies provide limited clinical benefits in patients with advanced HCC. Thus, new and more effective therapies for HCC are urgently needed. Most drug target discoveries and validation approaches employ cell culture-based screening methods or in vivo immunocompromised or immunodeficient mouse models (e.g., nude mice, NSG mice, etc.). However, multiple cell culture related artifacts (e.g., 2-D culture, high concentrations of growth factors in media, etc.) and use of immune-defective mouse models limit the rigorous identification of clinically relevant drug targets and ultimately negatively impact their translation to clinic. To overcome these limitations and to rigorously identify novel therapeutic targets in HCC, we combined two state-of-the-art approaches; namely an in vivo epigenome-wide CRISPR-based functional genomics screening with a humanized mouse model with functional human immune system. Using these systems, we identified the chromatin modifier NSD3 as a factor that promoted HCC tumor growth and metastasis in mice with functional human immune system. Mechanistically, NSD3 loss promoted NK cell-mediated HCC eradication and a highly-selective and efficacious inhibitor of NSD3, BI-9321, blocked HCC tumor growth in mice with human immune system. Based on these results, we hypothesize that NSD3-mediated suppression of NK cell-mediated anti-tumor immunity is necessary for the HCC tumor growth and metastasis and targeting NSD3 represents a novel therapeutic opportunity for treating HCC. The overall objective is to determine the in vivo role of NSD3 in driving HCC tumor growth and metastasis via suppressing NK cell-mediated anti-tumor immunity and evaluate in vivo pharmacological targeting of NSD3 for HCC treatment. In Aim 1, we will first determine the in vivo role of NSD3 in facilitating HCC tumor growth and metastasis. Next, we will determine the mechanism of suppression of NK mediated anti-tumor immunity by NSD3 and its role in the regulation of NSD3-mediated HCC tumor growth and metastasis. To answer these questions, we will use a novel liver fibrosis model that we have developed to study HCC tumor growth and metastasis in conjunction with immunocompetent humanized mice with transplanted human immune system. Additionally, using organ-specific and orthotopic spontaneous HCC metastasis models, we will study the role of NSD3 in HCC metastasis. In Aim 2, we will rigorously and comprehensively test the effectiveness of NSD3 inhibitors (BI-9321 and a NSD3-specific Proteolysis Targeting Chimera (PROTACs)) either alone or with other anti-cancer agents for HCC treatment in vivo. These studies will utilize established HCC cell lines and HCC patient-derived xenograft (PDXs) and use humanized mice transplanted with human immune system. Collectively, these studies will determine the role of NSD3 as a driver of HCC and establish the efficacy of NSD3 inhibitors for treating advanced HCC.
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