MDM2-p53 Antagonists Under Clinical Evaluation: A Promising Cancer Targeted Therapy for Cancer Patients Harbouring Wild-Type TP53

Mutation of TP53 occurs in about 50% of both sporadic and familial cancer cases. In the remaining malignant tumours harbouring wild-type TP53, it seems that p53 function is suppressed via other mechanisms, including MDM2 upregulation. In addition to frequent loss of p53 function in most types of tumours, the multi-functional transcription activity and tumour suppressor impact of p53 encouraged an enormous effort to introduce novel anti-cancer agents targeting p53. Different synthetic nongenotoxic inhibitors have been advanced to prevent the interaction between p53 and MDM2 and correct p53 dysfunction, of which some are still at early stages of development, and many have recently entered into clinical trials. In spite of the potential merits of targeting p53, including less damage to normal cells, fewer adverse events, and more efficiency, it has its potential drawbacks, which are needed to be addressed. Moreover, activated p53 impacts other biological processes making p53 restoration therapy more complicated. This issue can be resolved through the identification of biomarkers that predict sensitivity to these anti-cancer drugs, combined treatment, and optimization of p53-targeted therapy.

In this chapter, we review the role of TP53 as a tumour suppressor gene, targeting the interaction between p53 and MDM2 as a strategy for the treatment of malignancies and p53-MDM2 antagonists with emphasis on those that have been used in clinical trials. Other aspects of MDM2 inhibitors, including their predictive biomarkers, their side effects, resistance mechanisms, and combined treatment of MDM2 antagonists with other anti-cancer drugs, which potentially improve their clinical efficacy and patient stratification, will also be discussed briefly.

Keywords: Apoptosis, Clinical Trials, Combined Treatment, Growth Arrest, MDM2, MDM2 Inhibitors, P21WAF1, Peptide, Predictive Biomarkers, Resistance, Side Effects, Small Molecule, Targeted Therapy, TP53, Wild-Type.