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.

The study was funded by the
Children’s Cancer
Foundation, Baltimore, MD., and
Dani’s
Foundation, Denver, CO.

About Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown University
Medical Center and Georgetown University Hospital, seeks to improve the
diagnosis, treatment, and prevention of cancer through innovative basic
and clinical research, patient care, community education and outreach,
and the training of cancer specialists of the future. Lombardi is one of
only 39 comprehensive cancer centers in the nation, as designated by the
National Cancer Institute, and the only one in the Washington, DC, area.
For more information, go to http://lombardi.georgetown.edu.

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 our partnership with MedStar Health). Our
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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