Mutations in the TP53 gene are a feature of 50% of all reported cancer cases. In the other 50% of cases, the TP53 gene itself is not mutated but the p53 pathway is often partially inactivated. Cancer therapies that target specific mutant genes are proving to be highly active and trials assessing agents that exploit the p53 system are ongoing. Many trials are aimed at stratifying patients on the basis of TP53 status. In another approach, TP53 is delivered as a gene therapy; this is the only currently approved p53-based treatment. The p53 protein is overexpressed in many cancers and p53-based vaccines are undergoing trials. Processed cell-surface p53 is being exploited as a target for protein–drug conjugates, and small-molecule drugs that inhibit the activity of MDM2, the E3 ligase that regulates p53 levels, have been developed by several companies. The first MDM2 inhibitors are being trialed in both hematologic and solid malignancies. Finally, the first agent found to restore the active function of mutant TP53 has just entered the clinic. Here we discuss the basis of these trials and the future of p53-based therapy.
151 trials exploiting the p53 pathway have been conducted
TP53 gene therapy (Gendicine) using an adenovirus vector was approved by the Chinese State Food and Drug Administration (SFDA) in 2003
Small-molecule inhibitors of the p53–MDM2 interaction are efficacious in animal models and are in clinical trials for the treatment of solid and hematologic malignancies
Cyclotherapy—using a p53 activator to protect normal tissue from cytotoxic drugs and increase the therapeutic index in the treatment of TP53-mutant cancer—was effective in animal studies
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C. F. Cheok and D. P. Lane are adjunct at the Department of Biochemistry, Yong Loo Lin School of Medicine (National University of Singapore); C. S. Verma is adjunct at the Department of Biological Sciences (National University of Singapore) and the School of Biological Sciences (Nanyang Technological University); J. Baselga is Director Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. The authors thank T. L. Joseph for the models of MDM2 and MDM4.
The authors declare no competing financial interests.
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Cheok, C., Verma, C., Baselga, J. et al. Translating p53 into the clinic. Nat Rev Clin Oncol 8, 25–37 (2011). https://doi.org/10.1038/nrclinonc.2010.174
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