Building a Home for an “Orphan” Disease

Potential New Therapy for Ewing’s Sarcoma Discovered

February 15, 2010

Two Lombardi scientists have found a small molecule that could serve as the basis for a new treatment for Ewing’s sarcoma. If further studies continue to show positive results, they believe the novel agent could be the first targeted therapy to treat the disease, which is a rare childhood cancer.

In the United States, about 500 patients are diagnosed with Ewing’s sarcoma each year, and they are treated with a combination of five different chemotherapy drugs. Between 60-70 percent of patients survive over time, but many have long-term side effects that linger from the therapy.

Over 95 percent of patients with Ewing’s sarcoma have the same mutation – called a translocation – where the end of chromosome 22 becomes fused to the end of chromosome 11. This very specific mutation fuses two normally unrelated proteins into one oncogenic protein called EWS-FLI1.

Jeffrey Toretsky, MD, led the Lombardi research to discover the potential new treatment. He has been at the forefront of Ewing’s sarcoma research for a number of years. In 2009, Toretsky and colleagues published the third paper of a trilogy on this work in the prestigious journal, Nature Medicine. “This is the one where we’re throwing the ring into the pit of fire,” says Toretsky, in reference to the Lord of the Rings trilogy. The paper describes how the team used three research methods to validate that their new small molecule halts the growth of Ewing’s sarcoma cancer cells.

“In the first paper published in Biochemistry in 2004, Frodo gets the call to carry the ring,” explains Toretsky. Working with Lombardi colleague Aykut Üren, MD, the Toretsky-Üren laboratory was the first to create a recombinant EWS-FLI fusion protein. This allowed them to study the activity of the oncogene in depth.

“Then in the 2006 Cancer Research paper, we met the enemy and battled, like the end of the second book,” he says. This paper described discovering the interaction between EWS-FLI1 and an important binding partner called RNA helicase A (RHA). Through a series of partner proteins including RHA, EWS-FLI1 initiates and sustains the cancer. In order to stop the continued proliferation of the tumors, Toretsky and his team knew they needed to disrupt the binding between the oncogenic protein and its partners. Focusing on RHA, they worked to identify the specific region on RHA that stuck to EWS-FLI1. This painstaking work took over ten years from idea to implementation. Throughout that time, The Children’s Cancer Foundation of Baltimore, Maryland, supported Toretsky’s research, believing in the promise of his approach.

After completing this work, Toretsky began collaborating with Milton Brown, MD, PhD, director of Georgetown’s Drug Discovery Program. Together, the team searched for a molecule that would keep the two proteins separated. In other words, they sought an agent that would stick to EWS-FLI1 in the very place that RHA bound to the fusion molecule.

Brown’s laboratory is able to screen thousands of compounds for their potential drug-like properties in a matter of minutes instead of days or weeks. Using the known crystal structures of proteins, Brown and his team match the 3-dimensional structures of the target with a library of small molecules in silico, or on the computer. This way, they can conduct a very rapid assessment to find the best candidates for further testing in cells, which is a much more time consuming and expensive process.

In this case, Toretsky was able to use a library of small molecules loaned to Georgetown from the National Cancer Institute. The team of investigators screened 3,000 compounds for their potential to block the EWS-FLI1 interaction with RHA. The team found several molecules that bound to EWS-FLI1 and chose to pursue one of them, which seemed the most promising.

“We’ve taken this initial hit from the library and discovered the relationship between the small molecule and the EWS-FLI1 protein,” says Brown. “This is very exciting because it provides us the opportunity to bridge the gap between basic science and pre-clinical studies.”

The team is now conducting preclinical testing on the candidate drug. While several stages of the research process remain before the drug can move into the clinic, this could be the first targeted therapy to be developed for Ewing’s sarcoma.

“If we are successful, we’ll have taken a drug through the drug discovery pipeline for $7 million – much less than the $100 million that pharmaceutical companies cite,” says Toretsky.

Because of the relatively small number of patients diagnosed with the disease each year, there has been little research investment into new treatments. So-called “orphan” diseases such as Ewing’s, garner little interest from pharmaceutical companies who most often conduct drug development research. Georgetown’s Drug Discovery Program provides an academic solution, enabling basic laboratory research, like Toretsky’s, to progress to pre-clinical stages in the drug discovery pipeline.

“Ewing’s sarcoma is rare,” says Toretsky. “But our work has the potential to improve treatment not only for patients with this disease but for others who have cancers with similar molecular characteristics.”

Author: Allison T. Whitney