Targeting a Rare Cancer with Molecular Bullets

 

 

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It all started in a Thai restaurant in Bethesda, Md., in 1999. Jeffrey Toretsky, MD, met Aykut Üren, MD, for lunch to discuss how they could collaborate on a project together. Now nearly ten years later, Toretsky and Üren have found a small molecule that could serve as the basis for a new treatment for Ewing’s sarcoma.

At the time, Toretsky was a junior pediatric oncologist at the University of Maryland studying Ewing’s sarcoma, a rare cancer affecting teens and young adults caused by a single mutated protein. Üren, originally from Turkey, was completing his training at the National Institutes of Health (NIH).

The collaboration they developed over lunch that day in Bethesda centered on using Üren’s expertise in a new technique called phage display to develop novel treatments for Ewing’s sarcoma.

“I was ecstatic when Aykut called and said he would take the position,” recalls Toretsky. “This work could not have happened without him. It had to be a team effort.”

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.

Years of Work

Toretsky, a practicing pediatric oncologist as well as a research scientist, moved his lab from the University of Maryland to the Lombardi Comprehensive Cancer Center at Georgetown University in 2002. Since then, Toretsky has led the Lombardi research to discover the potential new treatment and has continued to treat patients in the Lombardi Children’s Cancer Center Pediatric Hematology/Oncology Clinic.

He has been at the forefront of Ewing’s sarcoma research for a number of years. Working with Üren, now an assistant professor at the cancer center, 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, and the team discovered an important binding partner called RNA helicase A (RHA).

“Aykut and I are still collaborating on the Ewing’s sarcoma work, but he now has additional projects of his own, and it’s great to see someone you have mentored succeed,” says Toretsky. “It made me feel really good to see NIH fund Aykut’s first R01.”

Üren received his first R01 grant from the NIH as primary investigator in 2006. The R01 is a peer-reviewed grant that is given to an investigator to support a defined research project within his or her area of expertise, and it is an important milestone in a researcher’s career.

Still, the work continued on Ewing’s sarcoma. Through a series of partner proteins including RHA, Toretsky knew that EWS-FLI1 initiates and sustains the cancer. In order to stop the continued proliferation of the tumors, he and his team 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.

Help from Friends

This painstaking work took over ten years from idea to implementation. Throughout that time, The Children’s Cancer Foundation (CCF), a Baltimore-based foundation that provides support for cancer care for children and research into childhood cancers, supported Toretsky’s research, believing in the promise of his approach.

In fact, the Foundation began supporting Toretsky as a fellow at the NIH in 1995, and has provided funding for his Ewing’s sarcoma research with Üren since 2000, totaling over $1 million in support of this specific project.

“The CCF was there from the beginning. They really supported this new idea and the dream of our research. And now, we have a result – we have a target for the disease,” says Toretsky.

With this data in hand Toretsky began collaborating with Milton Brown, MD, PhD, director of Georgetown’s Drug Discovery Program in 2007. 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.

The Payoff

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. Through screening first in silico and then through cellular screens, the team found one molecule that bound to the peptide very tightly.

“Up to this point we’ve been throwing stones at the disease, but we would like to be shooting arrows at the target,” says Toretsky. “And that is what we have been able to do working with Milt.”

This finding is also important for another reason – it demonstrates a proof of principle for a new method of designing drugs. The notion long accepted among scientists is that it is not possible to block protein-protein interactions given that the surface of these proteins is slippery, and much too flexible for a drug to bind to.

The drug discovery team is now working to make the compound target the pocket more specifically in order to create a better 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.

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, who treats several patients with the disease each year. “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.”

The Burroughs-Wellcome Fund (BWF) seemed to agree with Toretsky’s assessment. In early 2008, the BWF – an independent private foundation – awarded him a prestigious Clinical Scientist Award in Translational Research, worth $750,000. The NIH also recently funded a new R01 grant for Toretsky, which focuses on the role of cancer stem cells in the development of Ewing’s sarcoma.

By Allison Whitney, excerpted from the Summer 2008 issue of Lombardi Magazine