p53 Gene May Help Fight Tumors
Drug developers have long wondered whether p53, one of the most commonly mutated genes in cancer, would make a good target for cancer therapies. Three new studies in mice suggest that it might.
The gene normally helps suppress tumors, and many cancer patients are thought to acquire p53 mutations relatively early in the disease. It has not been known whether these mutations also contribute to cancer later on, once tumors have been established.
The mouse studies suggest that they do. The researchers tested this idea by creating mice with p53 genes that could be turned on and off. They allowed the mice to develop cancers before turning on the gene. When they activated p53, the results were dramatic.
Tumors disappeared as cancer cells died or stopped growing, sometimes within hours. In one study, mice with large tumors died because the anticancer response was so strong. Even restoring p53 for a short time caused tumors to disappear.
"The tumors went away when we activated p53," says Dr. Scott Lowe of Cold Spring Harbor Laboratory in New York. His group studied mice with a form of liver cancer, and their results appeared online in Nature on January 24.
Each group used different methods to study different tumors. But they all concluded that at least some tumors depend for their survival on blocking the p53 gene and the genetic program, or pathway, it controls.
"The p53 pathway must be kept silent in established tumors for their viability," says Dr. Tyler Jacks of the Massachusetts Institute of Technology, who led a companion study in Nature. "The pathway appears to remain important even in advanced tumors."
If the same is true in human cancers, then a potential therapy may be to reactivate a damaged p53 gene. The new results make this scenario seem plausible.
"The key point is that when you restore p53 in established cancer cells, the gene is engaged in the pathway," says Dr. Gerard Evan of the University of California, San Francisco, who led the third study. Their findings appeared in Cell on December 29, 2006.
"This is incredibly good news because it means that mending a lesion in the p53 pathway would restore the body's natural ability to kill or block the growth of tumors," says Dr. Evan.
The signals that activate p53 and lead to an antitumor response are specific to cancer cells. This means that restoring p53 is unlikely to have effects on normal tissues, and this was the case in most of the mouse experiments.
"These studies really do formally establish once and for all that the p53 pathway is a good therapeutic target," says Dr. Lowe. Developing ways to restore defective genes in cells will not be easy, he adds, but efforts are underway.
The mechanisms by which the cancers regressed varied with the tumors. Dr. Jacks' team found that lymphoma cells died while sarcoma cells stopped growing. In Dr. Lowe's study, the immune system played a role in causing liver tumors to regress.
Dr. Evan's group provides a cautionary note - the lymphomas they saw regress eventually returned. But the researchers are learning why this happened, and they remain optimistic.
"I believe that restoring p53 in human cancers is going to have a profound therapeutic effect that will be specific to cells with abnormal p53," says Dr. Evan.
By Edward R. Winstead