Dually Disrupted Driver Genes: Targeting the cell cycle and the p53 pathway in neuroblastoma and other paediatric cancers

Neuroblastoma, a tumour of the sympathetic nervous system, is the most common solid tumour in infants. Although most high-risk tumours initially respond well to treatment, half of the high-risk patients will eventually relapse. Survival chances then decline to less than 10%. In most high-risk neuroblastomas, especially in relapse tumours, cell cycle regulation (pRb pathway) and apoptosis (p53 pathway) are disturbed. In this thesis, we studied several of the genetic causes and their targeted treatment. We saw that cells with higher MDM2 (p53 pathway) or CDK4/6 (pRb pathway) levels were not more sensitive to MDM2 or CDK4/6 inhibitors. Additionally, we identified that simultaneous inhibition did not lead to synergistic results in neuroblastoma cells and mouse models. We also had a closer look at the CDKN2A locus, which is frequently mutated in cancer. This part of the DNA codes for two genes (p14 and p16) that each inhibit on of the aforementioned pathways. Inactivation of p16 resulted in a more stem cell-like phenotype and increased sensitivity to EGFR inhibitors, while this change was not seen after p14 inactivation. In addition, we describe the method and results of two Target Actionability Reviews. This systematic review method was designed in collaboration with the ITCC-P4 consortium. We describe and structure all published preclinical data and identify current knowledge-gaps, aiming to help guiding future studies. We did this for both MDM2 and CDK4/6 inhibitors in 16 paediatric solid and brain tumours.