Abstract 6826: PRMT5 inhibition is a promising therapeutic strategy for high-risk neuroblastoma

Abstract Neuroblastoma (NB), a pediatric solid tumor originating from the extracranial sympathetic nervous system, frequently persists as a metastatic, drug-resistant cancer despite recent improvements in dose-intensive chemotherapy, radiation, and surgical approaches. Identifying novel molecular targets and developing effective therapeutic regimens for NB is crucial. PRMT5, an arginine methyltransferase, has emerged as a potential target, with its inhibition demonstrating therapeutic effects in various cancer models. Multiple potent, small-molecule PRMT5 inhibitors are currently in clinical trials or development. In this study, we investigated the pre-clinical effects of a specific PRMT5 targeting small molecule inhibitor, PM5i, on NB growth. Analysis of multiple NB patient datasets revealed an inverse relationship between PRMT5 expression and NB patients' overall survival, underscoring PRMT5 as a potential therapeutic target. Our cytotoxicity and clonogenic assay data demonstrate that PM5i significantly inhibits NB proliferation and colony formation in a dose-dependent manner with IC50 values ranging from 1 to 4 µM across different NB cell lines (p<0.01). PRMT5 inhibition by PM5i significantly induced apoptosis with a 2-fold increase in Annexin V-positive cells compared to controls (p<0.05) and inhibited cell cycle progression by arresting cells in the S phase with the percentage of cells in the S phase increasing from 22% in controls to 45-50% in treated cells (p<0.01). These effects were consistent across different NB cell lines. To recapitulate in vivo tumor growth, we employed 3D spheroid models of NB. PM5i treatment significantly inhibited 3D spheroid growth and volume in a dose-dependent manner with about a 2-fold reduction compared to control treatments (p<0.01). Molecular analysis revealed that PM5i treatment downregulated the expression of genes involved in critical cell processes by 2 to 3-fold, including AKT, MAPK, and MYCN pathways in NB cells. These pathways are known to play crucial roles in NB pathogenesis and progression. Collectively, our data provide compelling evidence that PRMT5 targeting represents an effective therapeutic strategy for high-risk NB. The potent effects of PM5i on NB cell growth, survival, and key oncogenic pathways highlight the potential of PRMT5 inhibitors in NB treatment. Further development of PRMT5 inhibition strategies and their combination with current chemotherapies may pave the way for efficient clinical translation, holding significant promise for improving outcomes in high-risk NB patients. Citation Format: Parul Suri, Saurabh Agarwal. PRMT5 inhibition is a promising therapeutic strategy for high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6826.