Abstract
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.
Highlights
Medulloblastomas (MBs) are the most common primary malignant brain tumours of childhood[1]
MB has been classified into four molecular subgroups, namely: Wingless, Sonic Hedgehog, Group 3 (G3—worst prognosis) and Group 4 (G4—intermediate prognosis)[4]
We demonstrate that NPI0052 induces inhibition of proteasome activity with subsequent apoptosis activation in MB cells
Summary
Medulloblastomas (MBs) are the most common primary malignant brain tumours of childhood[1]. Survival of these children has improved in the past decades due to aggressive surgical resection, followed by high-dose craniospinal irradiation and chemotherapy. This treatment approach has come at a significant cost for survivors, with the majority of patients suffering from significant longterm neurocognitive, endocrine and other toxicities[2]. Recurrence is common and often proves fatal[3]. An adjuvant therapy holds the promise of offering a more effective and less toxic treatment for children with MB. MB has been classified into four molecular subgroups, namely: Wingless (good prognosis), Sonic Hedgehog (intermediate prognosis), Group 3 (G3—worst prognosis) and Group 4 (G4—intermediate prognosis)[4]
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