100 Quick summary: Researchers have discovered that adding a widely available thyroid hormone to standard chemotherapy significantly improves treatment outcomes for medulloblastoma, a malignant brain tumour that accounts for 20% of all childhood brain cancers. This differentiation therapy forces tumour cells to mature into a normal state instead of multiplying, which effectively blocks the persistence of therapy resistant cells that typically cause relapse. For healthcare practice and public policy, repurposing this inexpensive medication provides a rapid and safer clinical pathway towards preventing recurrence, protecting cognitive development, and enhancing the long-term well-being of paediatric patients. Researchers from Fox Chase Cancer Center have identified a widely used thyroid hormone that may significantly improve treatment outcomes for medulloblastoma, the most common malignant brain tumour in children. The study found that adding triiodothyronine (T3), an FDA-approved hormone used to treat hypothyroidism, to standard chemotherapy could help prevent tumours from growing back after treatment. The findings were published in the journal Molecular Therapy Oncology. “Most chemotherapy drugs work by killing rapidly dividing cells including cancer cells, but also many healthy ones. This is why chemotherapy can be so toxic,” said Zengjie Yang, MD, member of the Cancer Epigenetics Institute at Fox Chase. Medulloblastoma is typically treated with surgery, chemotherapy, and radiation, which can be lifesaving but are highly aggressive and often fail to prevent recurrence. Up to 30% of patients experience tumour regrowth. The research team, led by Yang, takes a different approach. The study focuses on differentiation therapy, which encourages tumour cells to mature into a normal-like state in which they stop dividing. “Differentiation is essentially cell maturation,” Yang said. “Instead of killing tumour cells directly, we push them to grow into mature cells that no longer multiply.” The researchers used T3, the active form of thyroid hormone, to trigger this maturation process. Differentiated tumour cells are far less likely to drive tumour growth or relapse. Because chemotherapy and differentiation therapy stop tumour growth in different ways, the researchers tested whether combining them would be more effective. In laboratory and animal models, chemotherapy followed by T3 Suppressed tumour growth more effectively than chemotherapy alone Allowed lower doses of chemotherapy to achieve similar results Prevented tumours from regrowing after treatment ended Worked against tumour cells resistant to chemotherapy In mouse models, tumours treated with chemotherapy alone eventually returned. When chemotherapy was followed by T3, tumour regrowth was markedly suppressed and survival was significantly extended. Because medulloblastoma primarily affects children, safety was a major focus of the study. Although T3 has been prescribed for decades, high doses can temporarily increase heart rate. The researchers found that T3 caused only a brief, mild increase in heart rate that was easily controlled with propranolol, a commonly prescribed beta-blocker. Importantly, propranolol did not reduce T3’s anti-tumour effects or add toxicity. “This showed us that potential side effects are manageable using existing medications,” said Yang. Medulloblastoma accounts for about 20% of all childhood brain tumours, with around 500 cases diagnosed annually in the US. Standard treatments have improved survival rates to over 70% for average-risk patients, but outcomes remain poorer for high-risk or relapsed cases, where recurrence rates are higher and long-term side effects from radiation and chemotherapy can include cognitive impairment, growth issues, and secondary cancers. The differentiation approach offers a complementary strategy that could reduce reliance on high-dose chemotherapy and radiation. By promoting cell maturation rather than solely relying on cell destruction, the therapy addresses a key limitation in current regimens: the persistence of therapy-resistant tumour cells that seed relapse. Because T3 is already FDA-approved, inexpensive, and well-studied, this strategy could move to patients faster than many experimental cancer drugs. A multicentre paediatric clinical trial is now underway with support from the Pediatric Neuro Oncology Consortium, a national network of children’s hospitals. The trial, known as PNOC044, will evaluate whether adding T3 to standard treatment can safely improve outcomes for children with medulloblastoma, including in relapsed or progressive cases. “Chemotherapy reduces tumour size by killing cells,” Yang said. “T3 helps prevent the remaining cells from coming back. Together, they may offer children a better chance at long-term survival with fewer side effects.” Experts note that repurposing approved drugs like T3 could accelerate progress in paediatric oncology, where developing new therapies is particularly challenging due to the need for stringent safety standards. The study’s preclinical data showed T3 not only enhanced chemotherapy efficacy but also maintained its benefits even in models of chemotherapy-resistant disease. This research builds on earlier work from the same team demonstrating T3’s ability to normalise tumour cells. With the ongoing trial, results could inform broader applications of differentiation therapy across other paediatric brain tumours. The approach represents a shift toward biologically informed treatments that target the developmental origins of medulloblastoma, which arises from immature cerebellar cells. By harnessing thyroid hormone signalling pathways involved in normal brain development, researchers aim to restore proper cellular maturation and halt uncontrolled proliferation.