Published in UAB Insight, Spring 2008
Skin Cream Targets p53 Tumor Suppressor Gene
With its ability to prevent genome instability, repair damaged DNA, and initiate apoptosis in cells with irreparable mutations, the p53 tumor suppressor gene plays a central role in the body’s capacity to fight off cancer. More than 50% of all human malignancies involve mutations in the p53 gene.
Scientists have recognized the potential value of therapies aimed at correcting mutant p53, but so far, gene transfer approaches have been unsuccessful. UAB researchers, led by Professor of Dermatology Mohammad Athar, PhD, have now found a way to deliver an agent that restores wild-type function to mutant p53.
Athar’s team developed and tested a novel topical formulation of the small molecule CP-31398. In a study funded by the National Cancer Institute, Athar and colleagues found the cream inhibits development of nonmelanoma skin cancer in mice exposed to ultraviolet B (UVB) light. The study, published in The Journal of Clinical Investigation, also reported CP-31398 reduced the size and number of existing tumors in mice with UVB-induced skin cancer (2007;117:3753-3764).
“The cream increases p53 function, which hyperactivates the body’s natural DNA repair mechanisms,” Athar says. “This is a major breakthrough in the fight against nonmelanoma skin cancers.”
Each year in the United States, exposure to UV radiation from sunlight or tanning beds causes more than 1 million cases of basal or squamous cell carcinoma, the American Cancer Society reports.
A More Effective Sunscreen
Adding CP-31398 to sunscreen could boost its effectiveness as a cancer-fighting tool if research shows the novel compound has the same effect in humans as it does in animal models.
Previous work has shown that CP-31398 increases tumor suppressor function in human skin cancer lines expressing mutant p53. “The compound holds promise as a chemopreventive agent for the many other cancers that feature p53 mutations,” says Athar. “Our study is the first to show a strategy aimed at restoring normal p53 function is successful in relevant mouse models, and research suggests a similar response in humans is likely.”
Experts around the country say findings from the study are encouraging. An editorial in the same issue notes, “Mutant p53 is an important target for cancer therapeutic development because mutations in this ‘guardian of the genome’ not only lead to tumor development and progression but are associated with poor response to therapy. These studies have important implications for chemoprevention as well as therapy of common, mutant p53-driven tumors.” (J Clin Invest. 2007;117:3753-3764.)
Future Applications
Athar hopes to secure funding to test CP-31398 in phase 1 and 2 clinical trials at UAB. He plans to pursue the compound’s use in other cancers with p53 mutations, particularly pancreatic and breast cancers — two of the common forms of cancer with frequent p53 mutations.
“The most important component of our findings is that if this approach proves correct, it will open doors for a large number of clinical trials for cancers in which we have identified p53 mutations,” he says.
For more information:
Dr. Mohammad Athar
1.800.UAB.MIST
mist@uabmc.edu