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Washington, DC – In a discovery that rebuffs conventional scientific thinking, researchers at the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC)
have discovered a novel way to block the activity of the fusion protein
responsible for Ewing’s sarcoma, a rare cancer found in children and
young adults.
In the paper published online July 5 in Nature
Medicine, they report discovering and successfully testing a small
molecule that keeps the fusion protein from sticking to another protein
that is critical for tumor formation. The researchers say this
interaction is unique – and is especially surprising since the Ewing’s
sarcoma fusion protein is extremely flexible, which allows it to change
shape constantly.
“Most targeted small molecule cancer drugs
inhibit the intrinsic activity of a single protein, but our agent stops
two proteins from interacting. This has never been shown before with a
cancer-causing fusion protein and represents a potentially novel
medical therapy in the future,” says the study’s lead investigator, Jeffrey Toretsky, MD, a pediatric oncology physician and researcher at GUMC’s Lombardi Comprehensive Cancer Center.
The
study could provide a model upon which to design treatment for other
disorders caused by the interaction between two proteins, and may be
especially useful in cancers caused by translocations of genes, such as
sarcomas and leukemias, the researchers say. Agents in use now that
work against fusion proteins inhibit a single protein to stop intrinsic
enzymatic activity; one example is Gleevec, used for chronic
myelogenous leukemia (CML). The Ewing’s sarcoma fusion protein, known
as EWS-FLI1, lacks enzymatic activity, “and this difference is why our
work is significant,” Toretsky says.
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 with side
effects from the treatment. Few additional treatment options are
available for patients whose cancer progresses, Toretsky says.
Ewing’s
sarcoma is caused by the exchange of DNA between two chromosomes, a
process known as a translocation. The new EWS-FLI1 gene 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.
It is a so-called disordered protein, which means it does not have a
rigid structure. A number of cancer-causing proteins are disordered.
In
their 15-year search for a new treatment for Ewing’s sarcoma, Toretsky
and his colleagues were the first to make a recombinant EWS-FLI1 fusion
protein. They used it to discover that 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, PhD, a postdoctoral researcher in Toretsky’s lab.
Then,
from a library of 3,000 small molecules loaned to Georgetown from the
National Cancer Institute, the researchers searched for a small
molecule that would bind on to EWS-FLI1. They found one, and further
discovered the same molecule, NSC635437, could stop EWS-FLI1’s fusion
protein from sticking to RHA.
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 many of these proteins are slippery – much too flexible for
a drug to bind to.
They tested the agent in laboratory cell
culture, and with the help of GUMC’s Drug Discovery Program, the
researchers designed a stronger derivative compound they called
YK-4-279. In this study, they tested YK-4-279 in two different animal
models of Ewing’s sarcoma and found that the agent significantly
inhibited the growth of tumors. There was an 80% reduction in the
growth of treated tumors compared to untreated tumors.
Toretsky
says that while the agent needs to be “optimized,” these results serve
as a proof of principle that inhibiting protein-protein interaction can
work as a novel therapeutic that will target only cancer cells.
“We may be able to use this strategy to attack proteins we thought to be impervious to manipulation,” he says.
The
study was funded by grants from the National Institutes of Health,
Children’s Cancer Foundation of Baltimore, MD, Go4theGoal Foundation,
Dani’s Foundation of Denver, the Liddy Shriver Sarcoma Initiative, the
Amschwand Sarcoma Cancer Foundation, the Burroughs-Wellcome Clinical
Scientist Award in Translational Research, and the GUMC Drug Discovery
Program.
Toretsky and co-authors Milton L. Brown, Aykut Üren
and Yali Kong are inventors on a patent application that has been filed
by Georgetown University related to the technology described in this
paper. The other authors report no related financial interests.
About Georgetown University Medical Center
Georgetown
University Medical Center is an internationally recognized academic
medical center with a three-part mission of research, teaching and
patient care (through Georgetown’s affiliation with MedStar Health).
GUMC’s mission is carried out with a strong emphasis on public service
and a dedication to the Catholic, Jesuit principle of cura personalis
— or “care of the whole person.” The Medical Center includes the
School of Medicine and the School of Nursing and Health Studies, both
nationally ranked, the world-renowned Lombardi Comprehensive Cancer
Center and the Biomedical Graduate Research Organization (BGRO), home
to 60 percent of the university’s sponsored research funding.
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