Pancreas cancer tumors spread quickly and are
notoriously resistant to treatment, making them among the deadliest of
malignancies. Their resistance to chemotherapy stems in part from a unique
biological barrier the tumor builds around itself. Now scientists at Fred
Hutchinson Cancer Research Center have found a way to break through that
defense, and their research represents a potential breakthrough in the
treatment of pancreas cancer.
In a paper published March 2012 in Cancer Cell,
senior author Sunil Hingorani, M.D., Ph.D., an associate member of the
Hutchinson Center's Clinical Research and Public Health Sciences divisions, and
colleagues describe the biological mechanisms of how the tumor barrier is
formed and detail a newly discovered way to break it down. Their research
significantly increased the length of survival in a genetically engineered
mouse model of the disease. Early clinical trials in humans are under way at a
few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the
Hutchinson Center's patient treatment arm.
Using a mouse model developed by Hingorani, the
scientists combined gemcitabine, the
current standard chemotherapy used to treat pancreatic ductal adenocarcinomas
(PDA), with an enzyme called PEGPH20.
When they infused the combination into specially engineered mice whose pancreas
tumors mimic those of human pancreas cancer, the combination broke down the
matrix barrier within the tumors and allowed the chemotherapy to permeate
freely and spread throughout the cancerous tissue. The result was a 70 percent
increase in survival time of the mice after the start of treatment, from 55 to
92 days.
"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," Hingorani said.
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 fibroinflammatory 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.
Hingorani and colleagues discovered that the
fibroinflammatory 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.
"That's the primary reason pancreas cancers are
resistant to everything we've thrown at them: because none of the drugs get
into the tumor. It's physics first, before we even get to the intrinsic
biology," Hingorani said.
PEGPH20 is a PEGylated form of rHuPH20 modified to
allow it to survive in the blood stream. 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.
"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," Hingorani said.
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The similar study is ongoing at Cancer Research UK's
Cambridge Research Institute, confirming the possible abilities of the enzyme PEGPH20
to stretch open the insides of blood vessels in mice. Here, it was validated
that greater amounts of two different chemotherapy drugs - gemcitabine and doxorubicin
– were able to reach pancreatic tumors.
Study author, Professor David Tuveson, group leader
at Cancer Research UK's Cambridge Research Institute, said: "Adding this
enzyme to treatments could be a game-changer for treatment of pancreatic cancer
if clinical trials show it can be used to treat patients safely. It made the
shape of blood vessels wider and rounder - essentially it's the difference
between changing the shape of blood vessels from a flat bicycle tire to a
pumped up one. This allowed drugs to easily travel to the tumor and destroy it,
when previously this was incredibly difficult. Also, the expanded blood vessels
now have holes that allow the drugs to reach the tumor more effectively.
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A formulation of the PEGPH20 enzyme has already been
approved by U.S. regulators for a different drug-delivery application. It is
injected under the skin to form a pocket that helps fluids and standard drugs
reach blood vessels. And a trial to test the PEGPH20-gemcitabine combination in
pancreatic cancer patients is already under way. Although other tissues in the
body contain HA, the enzyme doesn't seem to result in serious side effects in
animal studies, says Hingorani, who is working on the trial being run by
Halozyme Therapeutics (phase 2) from October 2011. He says if the treatment is
successful, other potential drugs for PDA that had been shelved should be
reexamined: "Maybe not enough of the drug got into the tumor," he
says.
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