Using molecular and cell-based models, researchers at Georgetown University Medical Center have refined the picture of how a cancer-promoting protein associated with Ewing's sarcoma functions.
And in the process, they have hit upon a possible strategy for treatment of the cancer, which is a rare and highly malignant cancer that most often strikes teens and young adults.
In the June 1st issue of the journal Cancer Research, published by the American Association for Cancer Research, the researchers report that the oncoprotein, EWS-FLI1, teams up with a helicase protein that bends the shape of RNA, and together they work to promote or repress transcription of various other proteins, leading to cancer development.
But because it is not possible to directly shut down helicase proteins, given their vital general role in protein transcription, and given that no one has figured out how to clinically inactivate EWS-FLI1 alone, the researchers propose driving a wedge-like drug between the two proteins that would eliminate their interaction.
"Proteins are three-dimensional structures, and the space between EWS-FLI1 and the helicase might be targetable by a small molecule that keeps the proteins apart," says the study's lead author Jeffrey Toretsky, M.D., an associate professor in the departments of Oncology and Pediatrics at the Lombardi Comprehensive Cancer Center. "It could render EWS-FLI1 harmless while not affecting its partnering helicase protein."
Toretsky adds that the findings may also help explain the workings of a number of difficult-to-treat sarcomas that are caused by the same sort of genetic rearrangements seen in Ewing's sarcoma. "Understanding the molecules EWS-FLI1 interacts with may provide insights into similar diseases," he said. "Very little work has been done to study the functional partners of these translocation proteins, and this study may offer a new research approach."
Ewing's sarcoma results in solid tumors in bone or soft tissue and is caused by a translocation between two chromosomes which fuses the EWS gene from chromosome 22 to the FLI1 gene of chromosome 11. This fusion produces the EWS-FLI1 fusion protein which is only found in tumors. This translocation is present in 95 percent of tumors, according to Toretsky, a recognized expert on Ewing's sarcoma. Chromosomal translocations are the cause of many sarcomas and leukemias, and the resulting fusion proteins represent targets for new therapies.
The potential for a drug that would target the fusion proteins in tumor cells was first put forward by scientist Paul Ehrlich more than 100 years ago. In Ewing's sarcoma, the proteins that are created from chromosomal translocations are unique and only occur in the tumor cells.