Differentiation-inducing triiodothyronine enhances chemotherapy and suppresses post-treatment tumor regrowth in medulloblastoma.
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Medulloblastoma (MB), the most common malignant pediatric brain tumor, is treated with intensive multimodal regimens that cause substantial long-term toxicity and fail to prevent recurrence in up to 30% of patients. We investigated triiodothyronine (T3), an FDA-approved thyroid hormone, as a differentiation-based therapeutic strategy for MB. Using a Sonic Hedgehog (SHH)-driven mouse model, two patient-derived xenografts (SHH and group 3), and drug-resistant TP53-mutant MB cells, we found that T3 and cytotoxic chemotherapy suppress tumor growth through complementary biological mechanisms: T3 promotes terminal differentiation of tumor cells, whereas cyclophosphamide (CTX) and irinotecan (CPT-11) induce caspase-3-dependent apoptosis. In vitro, T3 enhanced the tumor inhibitory effects of CTX and CPT-11, suppressed proliferation in chemotherapy-resistant cells, and promoted differentiation across MB subgroups. In vivo, sequential administration of T3 following chemotherapy suppressed post-treatment tumor regrowth and prolonged survival without increasing systemic toxicity. T3-induced transient tachycardia was effectively controlled with propranolol without compromising antitumor activity. Together, these findings support the potential of T3 as a clinically accessible differentiation-based therapy that enhances chemotherapy responses and suppresses post-treatment tumor regrowth in medulloblastoma.