Restoring the Tumor Suppressor Function of Mutated p53 Protein
INVESTIGATORS AT CINJ and the Institute for Advanced Study (IAS) in Princeton have identified and validated a drug compound that reactivates a primary function in a mutated form of the p53 protein — the ability to suppress cancer tumors.
More than three decades of research into the p53 protein has substantiated its role as one of the most important regulators of human cancer. P53 recognizes cellular stress and puts the brakes on cell proliferation. Loss of p53 function is one of the most common ways that cancer cells escape this control and proliferate freely.
The gene encoding p53 is mutated in more than half of human cancers. Most of these mutations result in a small change in the amino acid makeup of the protein‚ rendering it nonfunctional. Research on animal models of cancer has shown that restoring p53 function has been both highly therapeutic and‚ in some cases‚ curative. While rescuing the function of p53 with a drug is a highly attractive cancer therapeutic strategy‚ no drugs currently exist to restore that function in humans.
Researchers on this study include Cancer Institute of New Jersey resident member Arnold J. Levine‚ PhD‚ RWJMS professor and professor emeritus at IAS‚ who co–discovered p53 more than 30 years ago. The team developed a computer screening methodology that identified a compound that selectively kills cancer cells with the p53R175 mutation‚ which is the third most frequent type of p53 mutation in human cancer. The findings are published in Cancer Cell.
Utilizing anticancer drug screen data from the National Cancer Institute‚ in which more than 48‚000 compounds have been tested across a panel of 60 human tumor cell lines‚ investigators identified the compound known as NSC319726 as one that restores "wild–type" structure and function to the p53R175 protein. In addition‚ it activates the protein to induce a program to kill the cell (known as apoptosis). This observation occurs at doses of the compound that are non–toxic to normal (non–cancerous) cells.
When the compound was tested on human tumor cell lines with the mutation in experimental models‚ cell death was evident and tumor growth was blocked. Because of its ability to selectively kill cancer cells while leaving normal ones undisturbed‚ the authors say NSC319726 can be considered a lead compound for targeted drug development in p53 and may allow for the design of other compounds for different p53 mutations that fail to bind zinc.
"Some 32‚000 people in the U.S. are affected by this mutation annually. This is a large population that may find benefit from the NSC319726 compound in its ability to restore p53 tumor suppressor properties‚" says Darren Carpizo‚ MD‚ PhD‚ an RWJMS faculty member and a surgical oncologist at CINJ‚ who is the senior author of the research.
The team includes: Xin Yu‚ CINJ and RWJMS; Levine; and Alexei Vazquez‚ CINJ‚ RWJMS‚ and IAS.
The research was supported by CINJ‚ The Breast Cancer Research Foundation‚ and the National Institutes of Health.