Format

Send to

Choose Destination
Mutat Res. 2017 Jul;773:1-13. doi: 10.1016/j.mrrev.2017.02.003. Epub 2017 Feb 17.

When the guardian sleeps: Reactivation of the p53 pathway in cancer.

Author information

1
Department of Clinical Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address: olaf.merkel@meduniwien.ac.at.
2
Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Laboratory of Immunological and Molecular Cancer Research Laboratory of Immunological and Molecular Cancer Research, Paracelsus Medical University, Salzburg, Austria.
3
Department of Clinical Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
4
Department of Internal Medicine 1, Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, 1090 Vienna, Austria.
5
Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13a, 1090 Vienna, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna and Medical University of Vienna, Austria.
6
Department of Pathology, University of Cambridge, Lab Block Level 3, Box 231, Addenbrooke's Hospital, Cambridge CB20QQ, UK.
7
Department of Clinical Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13a, 1090 Vienna, Austria; Institute of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, Vienna, Austria. Electronic address: lukas.kenner@meduniwien.ac.at.

Abstract

The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes. Many malignancies display amplification of MDM genes encoding negative regulators of p53 and therefore much effort to date has concentrated on the development of molecules that inhibit MDM2, the most advanced of which are being tested in clinical trials for sarcoma, glioblastoma, bladder cancer and lung adenocarcinoma. These will be discussed as will recent findings of MDMX inhibitors: these are of special importance as it has been shown that cancers that become resistant to MDM2 inhibitors often amplify MDM4. Finally, we will also touch on gene therapy and vaccination approaches; the former of which aims to replace mutated TP53 and the latter whose goal is to activate the body's immune system toward mutant p53 expressing cells. Besides the obvious importance of MDM2 and MDMX expression for regulation of p53, other regulatory factors should not be underestimated and are also described. Despite the beauty of the concept, the past years have shown that many obstacles have to be overcome to bring p53 reactivation to the clinic on a broad scale, and it is likely that in most cases it will be part of a combined therapeutic approach. However, improving current p53 targeted molecules and finding the best therapy partners will clearly impact the future of cancer therapy.

KEYWORDS:

Gene therapy; MDM2; MDMX; TP53 gain-of-function; TP53 mutation; p53

PMID:
28927521
DOI:
10.1016/j.mrrev.2017.02.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center