CA --- April 19, 2005 --- A novel delivery system
that transports gene silencing nanoparticles into
tumor cells has been shown to inhibit Ewing’s sarcoma
in an animal model of the disease.
this classic “Trojan horse” approach, a protein called
transferrin that normally delivers iron into cells
is modified to also smuggle into tumor cells siRNA
(short interfering RNA) encased in nano-sized sugar
polymers. The siRNA was designed to target a specific
growth-promoting gene called EWS-FLI1 that’s active
only in Ewing’s sarcoma tumors.
inside these cells, the genetic machinery of the tumor
cells are effectively silenced or shut down, preventing
is the first study to show that systemic administration
of siRNA can inhibit disseminated tumor growth,” said
Siwen Hu, a postdoctoral fellow at Children’s Hospital
of Los Angeles and the University of Southern California,
and one of the study’s lead investigators.
conclude that this novel delivery system is a powerful
and simple method to induce gene silencing, with the
potential to move to clinical trials,” said Hu, who
presented the results at the 96th Annual Meeting of
the American Association for Cancer Research.
recent years, scientists have been intrigued by the
potential of siRNA to block the activity of genes
that promote the growth of tumors. Harnessing the
power of this new technology, however, has proved
daunting for a variety of reasons, including the ability
to deliver these bits of genetic material in high
concentrations to specific tumor sites, while avoiding
overcome these hurdles, the scientists employed a
sugar-containing polymer invented by chemical engineers
at the California Institute of Technology. For this
experiment, the polymer binds to and condenses the
engineered siRNA into nanoparticles that, in effect,
form a protective shield around their precious genetic
cargo. These nanoparticles, in turn, are attached
to transferrin, a protein that typically carries iron
molecules through the bloodstream until it meets up
with a transferrin receptor on the surface of another
cell. The transferrin binds tightly to a receptor
on the cell’s surface, where it is drawn inside and
surrounded by a small vesicle. The vessels are acidified,
causing the nanoparticles to release its contents
– the siRNA.
transferrin receptors are upregulated in tumor cells,
this delivery system will home in on tumor cells,
leaving normal cells in tact,” Hu said.
test their new delivery system, the scientists targeted
tumor cells from the patients of Ewing’s sarcoma,
a rare and often deadly bone cancer that generally
strikes young adults. Despite aggressive therapy,
about 40 percent of patients with Ewing’s family tumors
and 95 percent with metastases die as a result of
now recognize that Ewing’s sarcoma results when two
chromosomes break and trade their genetic content
in what’s technically called a “translocation,” activating
the oncogene EWS-FLI1 which triggers the tumor growth
characteristic for this cancer.
their experiment, siRNA was delivered to this growth-promoting
region of the tumor cell, effectively reducing cell
replication by 80 percent.
scientists then tried their novel technology in laboratory
mice grafted with human Ewing’s sarcoma tumors. Following
three consecutive days of treatment, the scientists
observed strong, but transient, inhibition of tumor
when used over longer durations (twice-weekly injections
up to four weeks), the results were striking.
treatments with this delivery system markedly inhibited
tumor growth, with little or no tumor growth in many
animals,” said Hu.
experiments will combine the novel delivery system
with small molecular anti-tumor agents, with hopes
of creating a new and effective way to treat Ewing’s
sarcoma and other tumors in the clinic.
Ewing’s patients are treated with combination of chemotherapeutic
agents, but despite aggressive treatments, the patient
outcomes are poor,” said Hu.
delivery system we’re developing can shield the drugs
from degradation before reaching the target sites,
while delivering siRNA for more specificity and potency
so as to lower the required dose for efficacy.”
study was a collaborative effort between the laboratory
of Timothy J. Triche, at Children’s Hospital of Los
Angeles; and the laboratory of Mark E. Davis, at Caltech.
Also participating in the study were Jeremy D. Heidel
and Derek W. Barlett, both at Caltech.
for this research came from the Las Madrinas endowment
in Molecular Genetics and Molecular Pathology at the
Children’s Hospital of Los Angeles, the Whitaker Foundation,
with the National Science Foundation funding part
of the work at Caltech.
the American Association for Cancer Research
Founded in 1907, the American Association for Cancer
Research is a professional society of more than 24,000
laboratory, translational, and clinical scientists
engaged in all areas of cancer research in the United
States and in more than 60 other countries. AACR's
mission is to accelerate the prevention and cure of
cancer through research, education, communication,
and advocacy. Its principal activities include the
publication of five major peer-reviewed scientific
journals: Cancer Research; Clinical Cancer Research;
Molecular Cancer Therapeutics; Molecular Cancer Research;
and Cancer Epidemiology, Biomarkers & Prevention.
AACR's Annual Meetings attract more than 15,000 participants
who share new and significant discoveries in the cancer
field. Specialty meetings, held throughout the year,
focus on the latest developments in all areas of cancer
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