Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In lab study, researchers find molecule that disrupts Ewing's sarcoma oncogene

15.04.2008
Researchers at Georgetown University Medical Center have found a small molecule they say can block the action of the oncogene that causes Ewing's sarcoma, a rare cancer found in children and young adults. If further studies continue to prove beneficial, they say the novel agent could be the first targeted therapy to treat the disease, which can produce tumors anywhere in the body.

The findings, presented today at the annual meeting of the American Association for Cancer Research (AACR) in San Diego, suggest that the unique way in which this molecule works -- through a so-called protein-protein interaction -- could provide a model upon which to design other therapies, says the study's lead investigator, Jeffrey Toretsky, M.D., a pediatric oncology physician and researcher at Georgetown University's Lombardi Comprehensive Cancer Center.

"I think this holds really wonderful promise as a unique way of targeting fusion proteins," he says. "People thought it wasn't possible to have a small molecule that can bind between flexible proteins, but we have shown that it can be done."

This study was conducted in laboratory cells, so additional research is necessary before the novel agent can be tested in patients, Toretsky says. In vivo studies are now underway, he says.

Ewing's sarcoma is caused by the exchange of DNA between two chromosomes, a process known as a translocation. The new gene, known as EWS-FLI1, is created when the EWS gene on chromosome 22 fuses to the FLI1 gene on chromosome 11, and its product is the fusion protein responsible for cancer formation.

In the United States, about 500 patients annually are diagnosed with the cancer, and they are treated with a combination of five different chemotherapy drugs. Between 60-70 percent of patients survive over time, but many have effects that linger from the therapy.

Toretsky has long led research into the causes of, and treatments for, Ewing's sarcoma. He and his laboratory colleagues were the first to make a recombinant EWS-FLI1 fusion protein. "We did this in order to find out if EWS-FLI1 might be binding with other cellular proteins," he says.

They found that, indeed, the fusion protein stuck to another protein, RNA helicase A (RHA), a molecule that forms protein complexes in order to control gene transcription. "We believe that when RHA binds to EWS-FLI1, the combination becomes more powerful at turning genes on and off," says the study's first author, Hayriye Verda Erkizan, Ph.D., a postdoctoral researcher in Toretsky's lab who is presenting the study results at AACR.

The researchers used a laboratory technique to keep RHA apart from the fusion protein, and found that both were important to cancer formation. Knowing that, they worked to identify the specific region on RHA that stuck to EWS-FLI1, and then collaborated with investigators in Georgetown's Drug Discovery Program to find a molecule that would keep the two proteins separated. In other words, such an agent would stick to EWS-FLI1 in the very place that RHA bound to the fusion molecule.

Using a library of small molecules loaned to Georgetown from the National Cancer Institute, the team of investigators tested 3,000 compounds to see if any would bind to immobilized EWS-FLI1 proteins. They found one that did, and very tightly.

This was a wonderful discovery, Erkizan says, because the notion long accepted among scientists is that it is not possible to block protein-protein interactions given that the surface of these proteins are slippery, and much too flexible for a drug to bind to.

"These are wiggly proteins yet this study shows that inhibition of protein-protein interactions with a small molecule is possible," Toretsky says. This possibility means that fusion proteins, such as those produced in other sarcomas as well as diverse disorders, might be inhibited, he says. This is a different process than other drugs that have been shown to work against fusion proteins, such as Gleevec, which blocks the enzyme produced by the chromosomal translocation responsible for chronic myelogenous leukemia (CML). "Gleevec inhibits a single protein, while we are trying to block the binding of two proteins, and we are very enthusiastic about the results so far," Toretsky says.

Toretsky recently received a $750,000 Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund (BWF), which he will use to accelerate these translational efforts to help treat Ewing's sarcoma, utilizing GUMC's drug discovery program.

Karen Mallet | EurekAlert!
Further information:
http://lombardi.georgetown.edu
http://www.georgetown.edu

More articles from Studies and Analyses:

nachricht Statistical method developed at TU Dresden allows the detection of higher order dependencies
07.02.2020 | Technische Universität Dresden

nachricht Novel study underscores microbial individuality
13.12.2019 | Bigelow Laboratory for Ocean Sciences

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A step towards controlling spin-dependent petahertz electronics by material defects

The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.

Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

Active droplets

21.02.2020 | Medical Engineering

Finding new clues to brain cancer treatment

21.02.2020 | Health and Medicine

Beyond the brim, Sombrero Galaxy's halo suggests turbulent past

21.02.2020 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>