Abstract 2605: Unveiling PTTG1IP’s oncogenic role in medulloblastoma tumors

Abstract Introduction: Medulloblastoma (MB) is the most common malignant brain tumor in children, responsible for 20% of all childhood brain tumor-related deaths. Standard treatment includes surgical resection followed by cranial spinal irradiation and chemotherapy. However, this approach causes severe toxicity, leading to long-term neurological and neuropsychological disabilities, and survival remains below 70%. Moreover, therapy-resistant cancer stem cells (CSCs) drive tumor growth, relapse, and progression. Group 3 MB, particularly the group 3γ subtype with c-Myc amplification, is associated with metastatic disease, high recurrence rates, and poor survival. There is an urgent need to identify novel molecular drivers to develop targeted, less toxic therapies. We hypothesize that Pituitary Tumor Transforming Gene 1 Interacting Protein (PTTG1IP) supports MB tumorigenesis. PTTG1IP facilitates nuclear translocation of PTTG1 (securin), a key mitotic regulator and transcription factor controlling oncogenes such as c-Myc. Meta-analysis reveals high PTTG1IP expression in group 3γ MB, correlating with poor survival. Preliminary data suggest that PTTG1IP regulates CSC stemness, proliferation, and therapy resistance through the PTTG1/c-Myc axis. Methods: MB cell lines (e.g., HD-MB03, D556, D425, and DAOY) and CSC-enriched populations were utilized. PTTG1IP expression was modulated using CRISPR/Cas9 knockouts or siRNA knockdowns. Functional assays included cell viability, sphere formation, migration, invasion, colony formation, and radiation sensitivity. Mechanistic studies involved RT-qPCR, immunoblotting, and chromatin immunoprecipitation (ChIP) to elucidate the PTTG1IP/PTTG1/c-Myc axis. Results: Loss of PTTG1IP significantly reduced MB cell viability, migration, invasion, colony formation, and stemness. Knockdown enhanced radiation sensitivity and decreased tumor sphere formation, suggesting that PTTG1IP is crucial for CSC survival. Mechanistic analysis revealed that PTTG1IP supports PTTG1 nuclear translocation and upregulates c-Myc, promoting cell cycle progression and CSC proliferation. Future studies will assess the role of PTTG1IP in MB tumorigenesis using in vivo models to validate its impact on tumor growth, CSC stemness, and radiation response. RNA sequencing will be performed to identify downstream targets and pathways regulated by the PTTG1IP/PTTG1/c-Myc axis. These studies will provide insights into the broader role of PTTG1IP in MB progression and therapy resistance. Conclusion: PTTG1IP plays a pivotal role in MB tumor growth and progression by regulating the PTTG1/c-Myc axis. Targeting PTTG1IP may represent a novel therapeutic approach to overcome therapy resistance and improve outcomes for MB patients, especially those with aggressive group 3γ tumors. Citation Format: Shahad M. Abdulsahib, Prabhakar Pitta, Saif Nirzhor, Panneerdoss Subbarayalu, Daisy Medina, Phat Do, Deepika Singh, Manjeet Rao. Unveiling PTTG1IP’s oncogenic role in medulloblastoma tumors [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 2605.