Tuesday, March 25, 2025
3/25/2025
Project Summary Epigenetic dysregulation is frequently observed in pediatric cancers, including neuroblastoma (NB), the most common extracranial solid tumor in pediatric patients. In my postdoctoral work, I identified that a cell state transition from an adrenergic to a mesenchymal epigenetic state is associated with the loss of GD2 expression and resistance to anti-GD2 therapy. Given the important role of anti-GD2 therapy in treating high-risk neuroblastoma patients, I designed a CRISPR-Cas9 screening platform to study epigenetic regulators of GD2 expression. I identified that individual knockout of several members of the PRC1.1/BCOR complex increases GD2 expression in GD2-low cell lines. AIM 1 will establish the relationship between the PRC1.1/BCOR complex and GD2 regulation by rigorously testing the necessity of the PRC1.1 complex to maintain low ST8SIA1 expression in mesenchymal cell lines. Mining genetic dependencies across 25 tumor lineages, I identified that the PRC1.1 complex is an enriched dependency in neuroblastoma independently of its ability to regulate GD2 expression. AIM 2 will validate that the gene PCGF1, the top enriched PRC1.1 subunit dependency in neuroblastoma, is a genetic dependency in multiple models of neuroblastoma. I will intersect chromatin and single-cell RNA-sequencing studies to determine the consequences of PCGF1 knockout on chromatin regulation and differentiation/cell state trajectories. No known small molecule inhibitors of PRC1.1 currently exist. The correlation of USP7 genetic dependency in the Dependency Map portal against all other gene dependencies revealed a strong correlation with PCGF1 dependency, suggesting a tractable pharmacologic approach to inhibiting PRC1.1. AIM 3 will establish USP7 inhibition as a mechanism to modulate PRC1.1 activity. These specific aims will test the capacity of highly potent and selective USP7 inhibitor to selectively upregulate GD2 expression and reduce neuroblastoma viability in vitro and in vivo. I anticipate that these findings will directly link PRC1.1 to epigenetic state and differentiation in neuroblastoma. Moreover, it will credential USP7 inhibition as a combinatorial therapy to restore the response to anti-GD2 therapy and directly target neuroblastoma cells. To complete the studies in this proposal, I will apply my strong expertise in epigenetics and pharmacology. To fill in critical gaps in knowledge and expand my scientific training, I’ve assembled a training plan that includes advisory committee members that are experts in immuno-oncology, single-cell sequencing, and USP7 chemistry. This proposal lays a strong framework for my long-term goal of establishing a lab that focuses on targeting epigenetic plasticity/heterogeneity as an intervention to overcome therapeutic resistance.
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