Pediatric medulloblastoma: molecular target discovered that could change treatment

A genetic signature has been identified that could explain the resistance to radiotherapy of Group 3 medulloblastoma, a malignant brain tumor that develops in the cerebellum, which is most common in childhood and often characterized by high resistance to radiotherapy and poor prognosis. The finding paves the way for new targeted therapeutic strategies with the aim of improving patient survival. The study, published in the journal Cancer Research, was led by Pasqualino De Antonellis, a researcher in the Department of Molecular Medicine and Medical Biotechnology at the University of Naples Federico II, in collaboration with Baylor College of Medicine (USA) and the SickKids Research Institute (Canada).

The research identified carbonic anhydrase 4 (CA4), an enzyme involved in the regulation of extracellular pH, as a potential pharmacological target. The researchers observed that overexpression of CA4 promotes the survival of cancer cells and reduces their response to radiation. Conversely, its inhibition makes tumors more sensitive to radiation therapy, with a significant reduction in recurrence and increased survival in preclinical models.

A particularly relevant aspect of the study is the use of acetazolamide (ACTZ), a drug already approved by the FDA and commonly used in pediatric neurology for the treatment of endocranial hypertension. In this context, ACTZ is repurposed(drug-repurposing) as a potential radiosensitizer for the treatment of Group 3 medulloblastoma with high CA4 expression. The results obtained show that the combination of ACTZ and radiotherapy produces promising effects in preclinical patient-derived models (PDX) characterized by high CA4 expression, with a reduction in genes associated with tumor recurrence and a slowing of tumor growth. In contrast, in models with low CA4 expression, treatment benefit was limited, highlighting the importance of molecular stratification of patients.

This finding opens up interesting clinical perspectives, with potential immediate spin-offs. Indeed, the use of ACTZ in a new therapeutic setting represents an example of rational repositioning of an already approved drug, with the real possibility of rapid clinical application in an area, such as relapsed medulloblastoma, where therapeutic options are currently very limited. Inthis direction, researchers are considering the initiation of targeted clinical trials to test whether ACTZ can enhance the efficacy of radiotherapy in children with Group 3 medulloblastoma who have high levels of the CA4 gene.