NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma

• Published in: Cell death & disease 2019-10, Vol.10 (11), p.785-13, Article 785
• Main Authors: Frisira, Eleni, Rashid, Fatima, Varma, Swastina Nath, Badodi, Sara, Benjamin-Ombo, Valentine Ayodele, Michod, David, Niklison-Chirou, Maria Victoria
• Format: Article
• Language: English
• Subjects: 38/1; 631/67/1922; 631/67/2332; 82/29; 96/106; 96/2; 96/31; Antibodies; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Biochemistry; Biomedical and Life Sciences; Blood-brain barrier; Brain cancer; Brain tumors; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cerebellar Neoplasms - drug therapy; Cerebellar Neoplasms - pathology; Cerebellar Neoplasms - radiotherapy; Chemoradiotherapy; Chemotherapy; Gamma Rays - therapeutic use; Gene expression; Glioblastoma; Humans; Immunology; Lactones - pharmacology; Life Sciences; Lipophilic; Medulloblastoma; Medulloblastoma - drug therapy; Medulloblastoma - pathology; Medulloblastoma - radiotherapy; Metastases; Morbidity; Multiple myeloma; Organoids; p53 Protein; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Pyrroles - pharmacology; Quality of life; Solid tumors; Targeted cancer therapy; Tumors; γ Radiation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2026-y

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.