Abstract 4131: Expanding the roles of 14-3-3 and Smad2/3 as coordinators of PKC-ι activity in medulloblastoma: a study based on PKC-ι specific inhibitor ICA-1S

Abstract Medulloblastoma is one of the most aggressive and common pediatric cancers, second only to leukemia, and the most common childhood brain tumor, comprising 20% of all pediatric brain cancers. Current treatment options involving radiation and chemotherapy as well as surgical resection are extremely invasive and often lead to patients living with long term neurological and endocrinological consequences. This study focuses on exploring the PKC-ι specific small-molecule inhibitor 5-amino-1-((1R, 2S, 3S, 4R)-2, 3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and its effects on medulloblastoma cell lines Daoy and ONS-76. Using the previously established IC50 values for both cell lines, this study demonstrates that PKC-ι inhibition by ICA-1S leads to significant downregulation of both 14-3-3/c-Raf/Erk and TGF-β/Smad2/3/β-catenin pathways. Our results showing the association and localization of PKC-ι with 14-3-3, Smad2/3, and Erk1/2 are likely driving this cross-talk communication between these two pathways. We also show that ICA-1S simultaneously induces apoptosis and pyroptosis in addition to reducing the migratory and invasive capabilities of medulloblastoma. Finally, as a proof of concept, we demonstrated that in-vivo treatment of ICA-1S decreased tumor volume in nude mice by approximately 50%. In summary, PKC-ι is likely an important oncogenic target in medulloblastoma and ICA-1S appears to be a promising potential medulloblastoma therapeutic that merits further research. Citation Format: Luke Lajmi, Wishrawana Sarathi Ratnayake, Sloan Breedy, Aaron Todman, Mildred Acevedo-Duncan. Expanding the roles of 14-3-3 and Smad2/3 as coordinators of PKC-ι activity in medulloblastoma: a study based on PKC-ι specific inhibitor ICA-1S [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 4131.