Targeting ERAP1 to disarm Gli activation in Sonic Hedgehog medulloblastoma

The Hedgehog (Hh) signaling pathway is a fundamental regulator of embryonic development, tissue patterning, and stem cell maintenance. The Hh pathway is activated by one of any three ligands: Sonic, Indian, or Desert Hh. Hh ligand binding to the receptor PTCH1, a 12-transmembrane cholesterol transporter, relieves PTCH1’s inhibition of SMO, a G protein-coupled receptor. Once active, SMO localizes to the primary cilium, where it promotes activation of the Gli transcription factors while preventing their proteasomal processing. Dysregulation of Hh signaling is implicated in several malignancies, most notably Sonic Hedgehog-type medulloblastoma (Shh-MB), the most common malignant pediatric brain tumor. In Shh-MB, loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO lead to constitutive activation of Gli transcription factors, locking cerebellar granule neuron progenitors in a proliferative state and preventing terminal differentiation. Despite the development of SMO inhibitors such as vismodegib and sonidegib, their use in children is contraindicated due to irreversible growth plate closure and skeletal toxicity. Moreover, resistance frequently emerges through mutations downstream of SMO, underscoring the need for alternative strategies that target the pathway at its terminal effectors.