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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Translating p53 into the clinic
Chit Fang Cheok1, Chandra S Verma, José Baselga
1p53 Laboratory, A*STAR, Singapore.
Abstract:
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.
Insights
Targeting the TP53 gene and its associated p53 pathway is a key strategy in cancer therapy. Various approaches, including gene therapy and MDM2 inhibitors, are being investigated in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TP53 gene mutations occur in 50% of cancers, with the p53 pathway often impaired in the remaining 50%.
- Targeted cancer therapies are advancing, with a focus on exploiting the p53 system.
Purpose of the Study:
- To review current and future p53-based cancer therapies.
- To discuss the rationale and ongoing clinical trials for p53-targeting agents.
Main Methods:
- Review of ongoing clinical trials for TP53-based therapies.
- Discussion of various therapeutic strategies including gene therapy, vaccines, protein-drug conjugates, MDM2 inhibitors, and mutant TP53 reactivators.
Main Results:
- TP53 gene therapy is the only approved p53-based treatment.
- p53-based vaccines, protein-drug conjugates, and MDM2 inhibitors are in clinical trials.
- The first agent to restore mutant TP53 function has entered clinical trials.
Conclusions:
- The p53 pathway is a significant target for novel cancer therapies.
- Diverse therapeutic strategies targeting TP53 are under active investigation and development.
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