Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Abstract

Background Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow up of young patients treated with SMOi for recurrent medulloblastoma. Methods Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. Results All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including two prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for three patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in two patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for one patient although her final height was below estimated target height. Conclusion Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

Medulloblastoma and Down Syndrome: An Extremely Rare Association

“…SHH inhibitors have become of great clinical interest in treating these tumors; actually many inhibitors are currently in different stages of development. Although preclinical results were quite promising, early resistance and growth and development impairment are challenging 25…”

Children's Oncology Group's 2023 blueprint for research: Central nervous system tumors

“…The use of smoothened (SMO) inhibitors for children with SHH-driven medulloblastoma remains limited due to concerns for developmental toxicity. 73,74 However, the implementation of an integrative risk-stratification system based on clinical, histological, and molecular criteria will allow more subgroup-specific therapy. 75 The focus of current COG front-line trials is to reduce treatment toxicity for low-and average-risk patients.…”

Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment

“…More recently, a retrospective study by Pereira et al reported responses in all rMB patients with somatic or germline PTCH1 mutations (6/8, 75%), including 2/8 (25%) with prolonged responses. Importantly, several of these studies reported growth plate fusion as a major side-effect of SMOi, limiting their upfront use to patients who are skeletally mature [ 175 , 176 , 177 ]. Furthermore, despite very good or complete responses, resistance to SMOi frequently occurred while on treatment [ 176 ].…”

“…Importantly, several of these studies reported growth plate fusion as a major side-effect of SMOi, limiting their upfront use to patients who are skeletally mature [ 175 , 176 , 177 ]. Furthermore, despite very good or complete responses, resistance to SMOi frequently occurred while on treatment [ 176 ].…”

“…In summary, the most effective and least toxic way to implement SMOi for the treatment of MB SHH remains to be defined; several studies have now reported growth plate fusion as a major side-effect of SMOi [ 175 , 176 , 177 ]. Pereira et al suggests SMOi for the treatment of rMB SHH should be time limited, a bridge to local therapy (neurosurgical resection/radiotherapy) and delivered in combination with other therapies to prevent selection of one or several resistant clones [ 176 ].…”