MODIFIED VITAMIN D SHOW PROMISE AS TREATMENT FOR PANCREATIC CANCER
A synthetic derivative
of vitamin D was found by Salk Institute researchers to collapse the barrier of
cells shielding pancreatic tumors, making this seemingly impenetrable cancer
much more susceptible to therapeutic drugs.
The discovery has led
to human trials for pancreatic cancer, even in advance of its publication today
in the journal Cell. By attacking a wound repair mechanism called
fibrosis, the findings may also have implications for other tough-to-treat
tumors, such as lung, kidney and liver cancer.
"While the
success of this drug in humans with pancreatic cancer is still unclear, the
findings in animal studies were strong, raising hope that ongoing clinical
trials will give people with this terrible disease hope for a truly new type of
therapy," says Ronald Evans, director of Salk's Gene Expression Laboratory
and senior author of the new paper.
Pancreatic cancer is
one of the deadliest forms of cancer, a fact highlighted in recent years by the
deaths of well-known figures such as Steve Jobs and Patrick Swayze. About
46,000 people are diagnosed in the United States each year and about 40,000
people die from the disease, according to the National Institutes of Health.
"For pancreatic
cancer, the five-year survival rate is the lowest of all cancers," says
Evans, holder of Salk's March of Dimes Chair and a Howard Hughes Medical
Institute investigator. "Part of the problem is that the science of
pancreatic cancer and its renowned resistance to therapy has not been
understood and that's why the work that we're doing is so important."
Evans and his
colleagues knew that the ability of the pancreatic tumor to communicate with
nearby cells -- called the tumor microenvironment -- is key to its growth.
Tumor cells send out signals that make the microenvironment inflamed and dense;
this "living shield" around a tumor not only helps the cancer grow,
but blocks the access of immune cells and chemotherapeutic drugs, making the
cancer particularly hard to treat.
Evans -- in
collaboration with researchers around the country involved in an
interdisciplinary initiative supported by Stand Up to Cancer -- wanted to
figure out how to restore this inflamed microenvironment to its normal or
"quiescent" state and weaken the wall around the tumor.
"There was
evidence that the activation of the microenvironment was theoretically
reversible, but nobody knew exactly what was responsible for the activation,
making it hard to turn off," says Salk postdoctoral research fellow Mara
Sherman, first author of the new paper.
Sherman, Evans and
their collaborators focused their attention on one component of this wall:
pancreatic stellate cells, which usually respond to small injuries by briefly
switching to an activated state, spurring new cell growth. In the case of
cancer, however, the stellate cells near a tumor -- in response to signals from
the tumor -- are constantly turned on. This chronic activation of the stellate
cells provides the tumor cells with extra growth factors and therefore helps
them proliferate, but also forms a wall-like barrier around the tumor that
protects it from chemotherapeutics and other cancer-fighting drugs.
In 2013, Evans' group
discovered that stellate cells in the liver could be inactivated by a
chemically modified form of vitamin D. They wondered whether the same could
hold true in the pancreas, despite the fact the vitamin D receptor was not
thought to be present in pancreatic tissue.
But indeed, when the
group of researchers examined the differences between activated and inactivated
stellate cells in the pancreas, they found that activated stellate cells near a
tumor had high levels of the vitamin D receptor. And when the researchers then
added modified vitamin D to activated stellate cells the cells quickly reverted
back to a healthy, inactivated state, stopping production of signals that spur
growth and inflammation.
"This was a big
surprise because vitamin D has been tried multiple times as a therapy for
pancreatic cancer and never worked," says Evans.
It turns out that
activated stellate cells rapidly break down normal vitamin D, preventing the
vitamin from binding to the receptor, Evans explains. But systematic analysis
of vitamin D analogues allowed the team to discover a modified form of vitamin
D that is more stable, resilient and effective in vitro.
To see whether this
new vitamin D-like compound could halt the growth of a tumor, Evans and the
team next studied its effectiveness in mice. The researchers found that
combining the drug with existing chemotherapeutics gave a 50 percent increase
in lifespan compared to chemotherapy alone.
"It's really
remarkable considering that vitamin D itself is not attacking the cancer
cells," says Michael Downes, a senior staff scientist at Salk and
co-corresponding author of the new work. "It's changing the environment to
a more favorable setting needed for the chemotherapy drugs to work."
Studies have shown
that people deficient in vitamin D are more likely to develop pancreatic
cancer. Based on the new results, Evans thinks that healthy levels of vitamin D
may help keep vitamin D receptor signaling in stellate cells normal and squash
a cancer's growth -- at least until a tumor itself forces the stellate cells to
"turn on."
"Recently, other
research groups have explored the idea of destroying the microenvironment
altogether to weaken a tumor," says Downes. "Our approach is very
different. Instead of destroying, we simply want to reprogram the tumor
microenvironment to a healthy state. This has the dual effects of delivering
more drugs to the tumor as well as replenishing the tissue with normal stellate
cells."
Evans group has
already teamed up with clinicians at the University of Pennsylvania to launch a
clinical trial testing the effectiveness of using their vitamin D-like drug in
cancer patients before pancreatic surgery. "Previous trials with vitamin D
failed because they didn't understand the need for a special form of vitamin D
and that for pancreatic cancer it must be used in combination with chemotoxic
drugs," Evans says. "So, by re-thinking the problem, have been able
to open up a new route to the treatment of pancreatic cancer and, looking
forward, hopefully other diseases as well."
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