Modern DNA sequencing technology is beginning to reveal the complete genetic makeup of various forms of cancer, and the results indicate that cancers are far more genetically complex than anticipated. One question raised by this new data is how to determine which of the hundreds of gene mutations found in tumors are important.
“Our idea is that tumor growth is probably driven by a few driver mutations and the vast majority of the observed mutations are just ‘along for the ride,’” says Adam Dupuy, associate professor of anatomy and cell biology and pathology at the University of Iowa Carver College of Medicine. “But the ‘drivers’ are not obvious. So, the question is, how do we distinguish drivers from passengers?”
It's a question that the National Cancer Institute (NCI) has defined as one of around 20 "provocative questions" in cancer research—major unsolved or neglected problems that if answered could lead to significant advances in oncology.
Dupuy is one of 57 researchers around the country who have received funding through the NCI's "Provocative Questions" initiative to focus on these problems. He will use his two-year, $275,000 grant to develop new tools to help identify driver genes in ovarian cancer, which could help researchers develop new therapies.
Dupuy's approach combines the ability of a common virus to infect cells with a genetic trick discovered in cabbage looper moths to insert gene mutations into ovarian cells and see which mutations drive tumor development.
The approach, called piggyBac, is a type of "jumping gene" that permanently inserts a piece of DNA – in this case the gene mutation of interest—into a cell's DNA. The modified virus is the vehicle that delivers the gene mutation to the ovarian cells. By constructing different adenovirus/piggyBac combinations, each carrying different mutations and then delivering them all in a single injection, the system provides an efficient way to test many mutations in one experiment.
Tracking which cells become cancerous will allow Dupuy and his team to identify cancer-driving mutations.
He notes that an increasing number of drugs are available that target specific gene mutations. If his research identifies one of those mutations as a driver of ovarian cancer, it could be quite feasible to initiate a clinical trial to test that drug against ovarian cancer, he says.
"We hope the development of this new tool will accelerate the process of validating candidate genes," says Dupuy, who also is a member of Holden Comprehensive Cancer Center at the UI. "It will allow researchers to quickly pick out the gene mutations that are most likely to be responsible for driving ovarian cancer from the many mutations that occur in these cancers. If the tool is successful, it could easily be adapted to be used for other cancers."