Potential Drug Candidate Restores p53 Tumor Suppressor Activity

Cancer researchers have begun experimenting with a potential drug that fights certain types of cancer by restoring the activity of a mutant form of the p53 tumor suppressor gene.

The gene encoding the p53 protein is mutated in more than half of human cancers, and rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Towards this end, investigators at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (New Brunswick, NJ, USA) developed a computerized screening program to identify compounds that could restore p53 activity.

Screening the [US] National Cancer Institute's anticancer drug data library, which contains information on more than 48,000 compounds that have been tested across a panel of 60 human tumor cell lines, revealed two compounds from the thiosemicarbazone family that demonstrated the ability to block growth of mutant p53 cancer cells, particularly growth of a p53R175 mutant. The p53R175 mutation is the third most frequent type of p53 mutation in human cancer.

Results of laboratory experiments that were reported in the May 25, 2012, online edition of the journal Cancer Cell revealed that one of the compounds, NSC319726, restored wild type structure, and function to the p53R175 mutant. This compound killed p53R172H “knockin” mice with extensive apoptosis and inhibited xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner. It was shown that at the molecular level this activity depended upon the ability of NSC319726 to bind to zinc ions, a property missing in the mutant form of p53. Control animals treated with the compound did not show any ill effects.

“The R175 mutation is the third most common p53 mutation – resulting in some 32,000 affected people in the United States annually. While more research is needed, this is a large population that may find benefit from the NSC319726 compound in its ability to restore p53 tumor suppressor properties,” said senior author Dr. Darren Carpizo, assistant professor of surgery at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. “Our findings support the growing trend in developmental therapeutics in which the efficacy of future cancer drugs will depend upon the knowledge of the patient’s tumor genotype.”

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University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School