Cells possess a variety of ways of dealing with mutations that can cause them to grow uncontrollably and eventually form a tumor. The tumor suppressor gene p53 plays a critical role in these cancer prevention processes, largely by triggering a form a cell death known as apoptosis.
Many research groups are working to develop strategies for boosting p53 levels in precancerous and malignant cells. However, since approximately half of all cancers have mutations that prevent p53 from triggering apoptosis, these approaches are limited in their effectiveness in treating cancer.
To overcome the mechanisms that cancer cells develop to circumvent p53's efforts to kill those cells, a team of investigators at the Beatson Institute for Cancer Research in Glasgow, Scotland, have turned to a related gene, known as p73, that also trigger apoptosis by a more circuitous but equally effective biochemical process. In a study published in the Journal of Clinical Investigation, this team, led by Kevin Ryan, Ph.D., found that a protein designed to turn on p73, delivered to tumors using a nanoparticle, kills both primary tumor cells and those that have spread from the original tumor.
Activating p73 to trigger apoptosis is a particularly promising approach to treating cancer because this gene is rarely mutated in human cancer cells. In this study, the researchers showed that turning on p73 starts the apoptosis process even when p53 is missing or damaged. To turn on p73, the investigators used a small fragment of the normal p53 protein, which they named "37AA." Although this protein triggered apoptosis in a wide variety of cancer cells, it had no effect on healthy cells.
Based on their results using cultured tumor cells, the investigators created a DNA plasmid that would code for the production of 37AA. They then attached this piece of DNA to a dendrimer nanoparticle and injected it every other day for 8 days into mice bearing human tumors. The results of this experiment showed clearly that tumors in the treated animals failed to grow and even shrunk in some animals. In contrast, animals treated with a control gene experienced continued tumor growth.
"Previously, we thought p73 was just a 'sleeping partner' of p53, so we're really excited that we've found a way to harness its function to treat cancer. While our studies are still at a preliminary stage, the next phase of our work is going to focus on developing a drug that mimics the effect of the 37AA protein. We hope this strategy could then be more readily tested for its potential development in human tumors," Dr. Ryan stated.
This work is detailed in the paper "A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo." This paper was published online in advance of print publication. A full copy of this paper is available free of charge through PubMed. View abstract.