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.
| Original language | English |
|---|---|
| Article number | 785 |
| Journal | Cell Death and Disease |
| Volume | 10 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 16 Oct 2019 |
Funding
We are grateful to Xinyu Zhang, Gary Warnes and Luke Gammon for their helpful advice, Dr. Owen Williams (ICH-UCL) for his help with irradiation of tumour organoids and Dr. Ashirwad Merve for his help with histological analysis of tumour organoid. We thank Dr. Silvia Marino and Dr. Xiao-Nan Li for the gift of patient-derived low-passage human MB cells. This work was funded by Children with Cancer UK fellowship (Reference No. 2014-178) awarded to M. V.N.-C. and grant W1075E from Great Ormond Street Hospital Children’s Charity awarded to D.M.
ASJC Scopus subject areas
- Immunology
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research
