Gene p53 thought to assist chemotherapy may help cancer thrive

May 16 2007

A gene thought to be essential in helping chemotherapy kill cancer cells, may actually help them thrive.

In a new study of chemo patients, scientists at the Georgia Institute of Technology and the Ovarian Cancer Institute found that 70 percent of subjects whose tumors had mutations in the gene p53 were still alive after five years. Patients with normal p53 displayed only a 30 percent survival rate. The findings raise the possibility of a new strategy for fighting cancer - namely, developing drugs to disable the functioning of this gene in the tumors of patients undergoing chemotherapy. The results appear in the May 16 edition of the open access journal PLoS ONE.

"P53 has long been recognized as a key player in directing chemotherapy-damaged cancer cells to self annihilate, but less attention has been paid to p53's role in repairing damaged cells,'said John McDonald, chair of Georgia Tech's School of Biology and chief research scientist at the Ovarian Cancer Institute.

When a cell is malfunctioning or injured, the gene p53 is called into action and tries to repair the cell. If the cell can't be repaired, p53 starts a process known as apoptosis that kills the cell. It's p53's role as one of the genes involved in initiating cell death that has led cancer researchers to long believe that the gene is essential to successful chemotherapy. The idea is that p53 assists in killing the cancerous cells that the chemo treatment injures.

But in this latest trial, Georgia Tech researchers found that p53 may be a ,double-edged sword." Chemotherapy patients whose tumors had a mutated p53 gene that didn't work had a much better survival rate than those who had normal p53.

In the study, researchers took malignant and benign ovarian tumors straight from the operating room and compared their gene expression profiles. Some of the cancer patients had been treated with chemotherapy prior to surgery, and some had not. At this point researchers didn't consider whether the patients actually had malignant tumors or had been treated with chemotherapy. However, they found that the gene expression profiles of the tumors clustered the chemotherapy-treated patients into two groups: those whose profiles were similar to cancer patients who had not been treated with chemo and those whose profiles were similar to patients with benign tumors.

As they continued their analysis, they found that the main difference between the groups' genetic profiles was the gene p53. While both groups had roughly the same amount of the protein encoded by p53, the cancer group had mutations in their p53 that caused the gene's corresponding protein not to function.The benign group's p53 was normal.

Five years later, only 30 percent of the chemotherapy cancer patients clustering in the benign group were alive, while 70 percent of those clustering in the cancer group were still alive. The stage of cancer at the time of surgery had no correlation to who survived and who didn't. What did seem to have an effect was whether p53 was working or not in the chemotherapy-treated tumors.

A standard belief in cancer research is that a working p53 is essential in helping chemo patients because it turns on the killing mechanism for the cells that were damaged by chemo. But McDonald points out that p53 can also help repair damaged cells. If p53 is repairing cancer cells, that may lead to cancer recurrence.

"We think p53 may actually help some cancer cells make a comeback," he said. "Based on our results, we propose that p53 may help repair some of the cancer cells damaged by chemotherapy leading to tumor recurrence and explaining the higher mortality rate of patients whose tumors had a functioning p53. If we are correct, inhibiting p53 in tumors being treated with chemotherapy may substantially improve patients' long-term survival."

McDonald and colleagues are continuing to test their theory by conducting studies in cell cultures and mice. If it bears out, then disabling the gene in tumors, through medications or new genetic techniques during chemotherapy may help patients survive.