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- Posted Tuesday March 20, 2012
Hutchinson Center and TGen scientists discover potential 'break through' in pancreatic cancer
New study shows how to defeat chemotherapy barrier in nation's
4th deadliest cancer
PHOENIX, Ariz. - March 20, 2012 - Scientists at Fred Hutchinson
Cancer Research Center and the Translational Genomics Research
Institute (TGen) have discovered a literal 'break through' in
pancreatic cancer.
A unique biological barrier that pancreatic cancer tumors build
around themselves have made them especially resistant to
chemotherapy treatments, according to the Hutchinson Center/TGen
study published today in the highly-regarded journal Cancer
Cell.
Pre-clinical experiments show that a combination of drugs could
break down the barrier surrounding these tumors, allowing
chemotherapy drugs to freely spread and permeate throughout the
cancerous tissue, according to the study.
"Discovering how to break through this barrier is a significant
finding that could eventually enable therapeutic compounds to be
much more effective in combating this deadly cancer and helping
patients," said Dr. Daniel Von Hoff, M.D., TGen's
Physician-In-Chief and one of the authors of the study, as well as
one of the world's leading authorities on pancreatic cancer.
"The barrier surrounding pancreatic ductal adenocarcinoma has
prevented therapeutics from reaching and effectively acting on this
cancer," said Dr. Von Hoff, who also is head of TGen's Clinical
Translational Research Division.
This research is now being tested for the first time in patients in
the U.S. and Europe, including those at Seattle Cancer Care
Alliance, the Hutchinson Center's patient treatment arm. These
tests have the potential to significantly increase the length of
survival in patients with pancreatic cancer, which is notoriously
fast-spreading and among the most lethal of all cancers, the study
says.
Dr. Sunil Hingorani, M.D., Ph.D., the study's senior author and an
associate member of the Hutchinson Center's Clinical Research and
Public Health Sciences divisions, developed the study's laboratory
model. By combining gemcitabine - the current standard chemotherapy
used to treat patients' pancreatic ductal adenocarcinomas - with an
enzyme called PEGPH20, scientists showed that the tumor barrier
could be broken down and the drug could more easily reach the
cancerous tissue.
"This represents the largest survival increase we've seen in any of
the studies done in a preclinical model, and it rivals the very
best results reported in humans," Dr. Hingorani said. "Being able
to deliver the drugs effectively into the tumor resulted in
improved survival as well as the realization that pancreas cancer
may be more sensitive to conventional chemotherapy than we
previously thought."
Unlike most solid tumors, pancreas tumors use a two-pronged defense
to keep small molecules, such as those contained in chemotherapy,
from entering: a vastly reduced blood supply and the creation of a
strong fibro-inflammatory response. The latter includes the
production of fibroblasts, immune cells and endothelial cells that
become embedded within a dense and complex extracellular matrix
throughout the tumor. One major component of this matrix is a
substance called hyaluronan, or hyaluronic acid (HA). HA is a
glycosaminoglycan, a complex sugar that occurs naturally in the
body and is secreted at extremely high levels by pancreas cancer
cells.
Dr. Hingorani, Dr. Von Hoff and their colleagues discovered that
the fibro-inflammatory response creates unusually high interstitial
fluid pressures that collapse the tumor's blood vessels. This in
turn prevents chemotherapy agents from entering the tumors. The
researchers found that HA is the main biological cause of the
elevated pressures that leads to blood vessel collapse.
Administering the enzyme/gemcitabine combination degrades HA in the
tumor barrier and results in rapid reduction of the interstitial
fluid pressure. This in turn opens the blood vessels and permits
high concentrations of chemotherapy to reach the tumor.
Details about the open clinical trial can be found at:
http://clinicaltrials.gov/show/NCT01453153.
Pancreatic ductal adenocarcinoma is the fourth leading cause of
cancer-related death in the United States. Overall five-year
survival is less than 5 percent with a median survival of four to
six months.
Grants from the National Cancer Institute, the Giles W. and Elise
G. Mead Foundation, Safeway and several individuals supported the
research. Collaborators at the University of Washington also
contributed to the study.
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Our researchers, including three Nobel laureates, bring a
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www.fhcrc.org.
Press Contact:
Dean Forbes
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