Abstract 5708: Investigating the role of SMYD3 in medulloblastoma progression and treatment response: Implications for targeted therapy

Abstract Medulloblastoma (MB), the most prevalent malignant brain tumor in children, presents significant treatment challenges, particularly in the aggressive Group 3 subtype, which is associated with poor prognosis. Current therapeutic strategies, including surgery, chemotherapy, and radiotherapy, often result in severe side effects and inadequate long-term outcomes. This study investigates the role of SMYD3, a histone methyltransferase known for its overexpression in various cancers, in mediating radioresistance in MB. We analyzed SMYD3 expression levels in MB cell lines and patient samples, revealing a notable overexpression in Group 3 MB, which correlated with diminished patient survival rates. Notably, ionizing radiation exposure resulted in a dose-dependent increase in SMYD3 expression, suggesting a potential adaptive response to treatment. Inhibition of SMYD3 using the small molecule BCI-121 significantly reduced cell viability and enhanced radiosensitivity in vitro. Preliminary in vivo studies utilizing a BALB/c nude mouse orthotopic MB model demonstrated promising outcomes, indicating that targeting SMYD3 may improve therapeutic efficacy. Our findings underscore the critical role of SMYD3 in promoting radioresistance in MB and suggest that SMYD3 inhibition could be a viable strategy to enhance the effectiveness of radiotherapy, particularly in aggressive MB subtypes. Further investigations are warranted to elucidate the underlying mechanisms and to explore the potential for combination therapies aimed at improving treatment outcomes in MB. Citation Format: Swapna Asuthkar, Erick Benjamin Saldes, katherine Shishido, Ilango Balakrishnan, Sujatha Venkataraman. Investigating the role of SMYD3 in medulloblastoma progression and treatment response: Implications for targeted therapy [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 5708.