News and Information

Centerpoint Fall 2009 (PDF)

Researchers Enlist microRNAs to Combat Lung and
Other Cancers

microRNAs RNA stands for ribonucleic acid. RNA used to be thought of as DNA’s messenger, essentially carrying the blueprints for making proteins. That’s a decent snapshot of what many RNAs do, but not all types of RNA are strictly genetic delivery services. In 1993, scientists identified the first microRNA. As the name implies, a microRNA is a much shorter sequence than RNAs discovered earlier. But what they lack in size they make up for in power. This microRNA was a foreman, not a messenger. It played a key role in putting genes to work – and telling them when to stop working – in building a developing organism. Other microRNA were subsequently discovered that perform similar jobs. These little foremen offer fascinating possibilities in cancer research. The kind of rapid cell division that goes on in the embryonic stage is similar to what happens in a cancerous growth. Could scientists enlist microRNA to fulfill the same role in cancer that they do in embryonic development? Could microRNA tell those rapidly dividing cells that it’s quitting time?

Imagine you could order a cancerous tumor to stop growing. Imagine a simple test could predict your risk for hard-to-detect cancers and get you into lifesaving treatment early. Yale Cancer Center members are conducting research that shows the promise of microRNAs to do both. Biologist Frank Slack, PhD and radiation oncologist Joanne Weidhaas, MD, PhD are leaders in this growing field. Slack’s work has shown microRNAs can suppress lung cancer in laboratory animals. Together they’ve found a mutation in a microRNA binding site that signals risk for a particularly dangerous form of lung cancer. They are working to translate these groundbreaking discoveries in the lab into new clinical treatments.

When Slack, an Associate Professor of Molecular, Cellular & Developmental Biology, discovered the microRNA let-7, he wasn’t thinking about medical implications. He was simply trying to better understand the basic biology underlying development. When let-7 was missing in the roundworms Slack studied, the cell division typical of the embryonic stage never stopped and eventually killed the worms. The implications for cancer were clear. “During development is really when the cell cycle is working overtime,” he explained. “We’re essentially a mini-tumor as an early embryo.”

Meanwhile Joanne Weidhaas, an Associate Professor of Therapeutic Radiology, was interested in discovering ways to make cancer cells more sensitive to radiation and in finding out why some cells resisted radiation treatment. She chose to be a radiation oncologist because it combined patient care with the opportunity to do basic research. The roles complement each other. “I learn something from every patient,” she says.

Their collaboration began through the roundworm known as Caenorhabditis elegans, or C. elegans. The organism is a lab favorite because it’s easy to work with and shares 60 percent of its genes with humans. At Yale, there’s a weekly meeting for scientists using C. elegans to compare notes. Slack presented his let-7 work to the group. He found that let-7 regulates ras genes, which play a role in about one quarter of human cancers. Weidhaas was studying ras’s role in radiation resistance. So they began working together to see if let-7 and other microRNAs could help patients benefit more from radiation.

Targeting microRNAs could be a particularly efficient way to combat cancer. They regulate multiple genes, so they could control a broad spectrum of oncogenes, the genes that cause cancer when activated. Easily made in a test tube, customized microRNAs could be made by labs for patients whose natural microRNAs are not doing their job of suppressing oncogenes. As science moves toward personalized medicine, treatments tailored to the particular genetics of an individual cancer, microRNAs could provide keys to customizing treatment plans.

Weidhaas and Slack caution that a “eureka” moment in the lab does not signal immediate changes in clinical therapy. Slack notes that most molecular therapies do not make it into the clinical stage. But he adds that microRNAs have the advantage of being natural molecules, decreasing the likelihood that the body would reject them.

The pair have written widely on the role of microRNAs in lung cancer and have completed yet-to-be-published work that shows their importance in other cancers. The lung cancer risk finding was especially important because the disease is so often caught late when treatment options are limited. The pair formed a company to develop a simple blood test that could screen for the form of lung cancer that occurs when genes have trouble binding with let-7. Weidhaas was particularly interested in lung cancer, having lost an aunt to the disease. “We try our best and give it the most, but it’s still a very deadly cancer,” she reflected. Through research, she can create new possibilities to one day offer her patients. “I just feel really blessed,” she said, “really lucky to have that opportunity.”