Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood–brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours.
Group 3 medulloblastoma (MB) is the most aggressive and least characterised of all MB subgroups. These tumours are highly metastatic and patients undergo aggressive treatments leaving survivors with severe side effects. The standard of care for these patients consists of surgical resection followed by gamma-radiation and chemotherapy. Whilst this conventional therapy is successful in the majority of cases, however, many survivors are left with lifelong severe neurocognitive and physical sequelae. Interestingly, the proteasome plays a vital role in the pathogenesis of different tumours, therefore proteasome inhibition can be used as a new strategy for treating MB. NPI-0052 is a proteasome inhibitor that can penetrate the blood-brain barrier with a good safety profile, making it an appealing treatment for brain tumors. In the present study, we evaluate the anticancer activity of NPI-0052 in a range of MB patient derived MB cells and cell lines. Our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. We also show that the p53-family plays a substantial role in NPI-0052’s mechanism of action. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with gamma-radiation, a component of the current MB therapy, in both cells and tumour organoids. Our work underscores the use of NPI-0052 as a novel therapy for reducing the doses of gamma-radiation in G3-MB patients.
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