Bracing p53 for the War on Cancer

Sometimes called the "guardian of the genome," a protein called p53 responds to DNA damage by either shutting down cell division or causing the cell to commit suicide. Either way, p53's action helps short-circuit tumor formation by preventing cells that have suffered malignant mutations from continuing to grow. Yet the p53 gene itself is susceptible to damage, which is thought to contribute to the development of half of all cancers. In tomorrow's Science, researchers describe a drug that may be able to restore the normal function of some mutated p53 proteins and might therefore point the way to a new kind of cancer therapy.

To halt cell division or trigger cell suicide, p53 needs to regulate the activity of various genes, which requires that it first bind to the DNA of the genes' regulatory sequences. Researchers have found that many mutations that disable p53 cause the protein to misfold, thereby producing a molecule without the rigid three-dimensional conformation it needs for this binding.

Before searching for a molecule capable of bracing an aberrant p53 in the correct position to attach to DNA, cancer biologists Farzan Rastinejad and Barbara Foster of Pfizer Central Research in Groton, Connecticut, needed a quick way to tell whether a compound was working. They hit on the idea of using a well-known antibody that recognizes a part of p53 that is exposed only when the protein is in the right conformation. Ultimately, they screened more than 100,000 compounds with the antibody, first identifying compounds that could increase its binding to normal p53, then testing the successful compounds on mutant p53 in the test tube. The compounds that passed that test then went on to the next phase, in which Rastinejad's group looked to see which ones could correct a mutant p53 protein in cultured tumor cells. After winnowing the pack further, they showed that the remaining candidate drugs curbed cancer growth in mice.

Their results are just a first step on the long road toward making a drug that can be used in humans. Nevertheless, they represent "an exciting proof of principle of what promises to be a new form of therapy," says Bert Vogelstein, a cancer biologist at The Johns Hopkins University School of Medicine in Baltimore, Maryland. What's more, Rastinejad adds, because misfolded proteins are implicated in other disorders, including Alzheimer's, cystic fibrosis, and the brain diseases thought to be caused by infectious proteins called prions, "this approach may pertain to a lot of diseases."

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