EXTH-27. Repurposing Thyroid Hormone to Improve Chemotherapy Outcome for Medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with current treatments primarily involving surgical resection, radiation therapy, and chemotherapy. However, these conventional approaches are frequently associated with significant long-term toxicities and the development of treatment resistance, highlighting the urgent need for improved therapeutic strategies. Recent studies have shown that triiodothyronine (T3), the active form of thyroid hormone, suppresses MB growth by promoting the terminal differentiation of tumor cells. Unlike traditional cytotoxic agents that induce apoptosis, T3 functions via a differentiation-based mechanism, suggesting a potentially complementary mode of action. In this study, we explore the therapeutic potential of combining T3 with cytotoxic agents such as irinotecan (CPT-11) and cyclophosphamide (CTX) to enhance treatment efficacy. Our results demonstrate that T3 exhibits additive effects with chemotherapy in inhibiting tumor cell proliferation and allows for dose reduction of cytotoxic agents, thereby potentially mitigating systemic toxicity. Additionally, T3 effectively suppresses the growth of tumor cells resistant to cytotoxic drugs, indicating its promise in overcoming drug resistance. Given its well-established safety profile and FDA approval for hypothyroidism, repurposing T3 for MB therapy may accelerate clinical translation. Our findings provide a strong rationale for integrating T3 into standard chemotherapy regimens to improve therapeutic outcomes and reduce adverse effects in MB patients. Further clinical studies are warranted to evaluate this combinatorial approach.