Friday, April 18, 2025
4/18/2025
Targetable epigenetic modifiers that promote neuroblastoma malignancy and plasticity - ABSTRACT Neuroblastoma is an embryonal cancer of the sympathetic nervous system (SNS), caused by a developmental block, that disproportionally causes 15% of pediatric cancer-related deaths. Patients with high-risk neuroblastoma are treated with long-term intensive multi-modal therapies. Unfortunately, the 5-year overall survival of high-risk patients is about 50% with limited options for the rest who have poor response or disease relapse. Identifying the vulnerabilities of high-risk neuroblastoma and understanding the mechanism of therapy resistance are critical for achieving more effective therapies. Recent transcriptomics studies and genome wide CRISPR screening have identified core regulatory circuitry transcription factors (CRC TFs), which determine SNS cellular or lineage identity during development, as neuroblastoma dependency genes. High-risk neuroblastoma is a MYC-driven cancer with 50% of high-risk neuroblastoma having MYCN amplification while another 10% has high c-MYC activity. Targeting CRC TFs or MYC TFs (N-MYC or c-MYC) is technically challenging. Our preliminary data from the laboratories of Dr. Jun Yang and Dr. Kevin Freeman demonstrate that targetable epigenetic modifiers including histone deacetylases (HDAC) and histone lysine demethylase 4 family (KDM4) connect MYC to neuroblastoma specific CRC TFs. Our central hypothesis is that MYC oncogenes are reliant on epigenetic factors to reenforce CRC TF regulated developmental blocks. Therefore, this proposal will focus on understanding the interactions of MYC, CRC TFs and epigenetic modifiers in neuroblastoma pathogenesis, and how to target their interactions for development of novel therapies. Specifically, in Aim 1, we will determine the mechanism of how the bHLH transcription factor TCF4 promotes MYC’s enforcement of pro-oncogenic CRCs, which we propose is through TCF4 recruitment of HDACs and that understanding this mechanism will improve the application of HDAC therapy against high-risk neuroblastoma. In Aim 2, we will determine the mechanism by which KDM4 inhibition disrupts CRCs and test the translational feasibility of KDM4 blockade when combined with standard of care in high-risk neuroblastoma models. The outcome of this study will result in a gain of mechanistic insights on how epigenetic modulators wire MYCs to CRC TFs, and how to better target clinically relevant oncogenic drivers for NB clinical trials.
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