p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression, function and stabilization of p53 are governed by a complex network of regulators including
p14(ARF) and MDM2. MDM2 is the main negative regulator of p53 activity and stability. Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours
neuroblastoma and
sarcoma frequently retain wild type p53. Nevertheless, in childhood
cancer the p53 pathway is commonly impaired due to upstream MDM2-p14(ARF)-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are very rare. In
cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53 levels, potently "re-activate" dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53 interaction inhibitors, including cis-
imidazolines analogs (Nutlins), are potentially very effective agents in
neuroblastoma and
sarcomas. Predictive
biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors. Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, it is essential that other predictive
biomarkers are investigated. The serum concentration of
macrophage inhibitory cytokine- 1 (MIC-1) may be a good pharmacodynamic
biomarker based on recent findings. In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeutic approach in poor prognosis paediatric
malignancies without p53 mutations.