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.
Deep Brain Stimulation Provides Sustained Relief for Severe Depression
19.03.2019 | Universitätsklinikum Freiburg
AI study of risk factors in type 1 diabetes
06.03.2019 | University of Gothenburg
DESY and MPSD scientists create high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might find intriguing applications in petahertz electronics and for spectroscopic studies of novel quantum materials.
The nonlinear process of high-order harmonic generation (HHG) in gases is one of the cornerstones of attosecond science (an attosecond is a billionth of a...
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
22.03.2019 | Life Sciences
22.03.2019 | Life Sciences
22.03.2019 | Information Technology