- Crossing borders in targeted therapy
- Award date
- 6 September 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Neuroblastoma is the most commonly diagnosed childhood cancer and accounts for about 15% of all pediatric malignancies deaths. Thus far, the treatment options of neuroblastoma is limited with only a 30-40% long term survival rate in high-risk patients.
In this thesis, we describe the isolation and propagation of neuroblastoma organoids called tumour initiating cells (TICs). We show that these cells recapitulate the genotype and phenotype of the primary tumours from which they are derived from. These organoid systems might thus improve in vitro pre-clinical drug testing studies in neuroblastoma.
The genomic landscape of neuroblastoma constitutes of whole chromosome gains and losses as well as deletions and amplification of specific regions of the chromosomes. MYCN amplification, 17q gain, 1p36 and 11q losses are strong prognostic indicators of poor patient outcome. Amplification of chromosome 7q36 which harbours EZH2 has been observed in neuroblastoma. We carried out the pre-clinical evaluation of EZH2 histone methyltransferase-specific inhibitors in neuroblastoma. We show that EZH2 is important in neuroblastoma cell survival independent of its histone methyltransferase function.
Aside from the genomic events observed in neuroblastoma, several oncogenes and tumour suppressors are frequently deregulated in neuroblastoma. The B-cell lymphoma protein 2 (BCL2) is frequently upregulated in neuroblastoma. We described the pre-clinical evaluation of the BCL2-specific inhibitor venetoclax in neuroblastoma. We show that response to venetoclax is strongly correlated to BCL2 protein and mRNA levels. Resistance to venetoclax could be overcome by the combined inhibition of BCL2 and MCL1 as well as p53-mediated activation of the intrinsic apoptotic pathway.
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