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

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.

Proteasome inhibition—a new target for brain tumours

“…Evidence from Tsvetkof et al suggests that malignant cells are addicted to the UPP for survival 9 , and are therefore more sensitive to its inhibition than normal cells. Our recent work confirms this and shows that high proteasome activity in MB cells is associated with poor prognosis 8 . MB is the most common solid primary malignant brain tumour of children 10 .…”

“…The UPP has also been shown to contribute to the neurogenesis of cerebellar progenitor cells due to its role in regulating the degradation of transcription factors involved in neuronal cell differentiation 7 . The focus of our work was to study the activity of the UPP in medulloblastoma tumours (MBs), a cancer that originates from the cerebellum 8 . Evidence from Tsvetkof et al suggests that malignant cells are addicted to the UPP for survival 9 , and are therefore more sensitive to its inhibition than normal cells.…”

“…The former is important in aggressive MBs because they express wild-type p53 and high levels of p73 14 . Therefore, increasing the p53 or p73 tumour suppressor function via proteasome inhibition is a feasible treatment option for p53 wild-type or p73 expressing cancers 8 . Importantly, proteasome inhibition by proteasome inhibitors (PIs) has minimal toxic effects on normal cells 15 .…”

Cerebral organoids: emerging ex vivo humanoid models of glioblastoma

“…Whether these GBM subpopulations will be successfully integrated in the hybrid model remains to be seen. Besides the aforementioned efforts, organoid systems have been significantly leveraged in drug screening studies whether for the purpose of elucidating mechanisms of synergistic toxicity in medulloblastoma models [ 61 ] or in the context of neurodegeneration [ 62 , 63 ] and epilepsy [ 64 , 65 ]. Adding more layers of cellular complexity is expected to improve accuracy and efficient modelling of disease.…”

Role of MicroRNAs in the Development and Progression of the Four Medulloblastoma Subgroups

“…The therapy of choice for medulloblastoma is surgical removal of the tumour followed by chemotherapy and radiotherapy [ 18 ]. Ideally, the operation should completely remove all cancer cells, but it may be impractical if the tumour is in an inaccessible area or if there is a risk of damaging an area of vital importance or compromising the physical and cognitive functions of the patient [ 19 ]. Complementary therapy to surgery is direct radiotherapy to the head and spine (craniospinal radiotherapy) [ 20 ].…”