and Medicine for Seniors
Glimmer of Hope in Battle Against Pancreatic Cancer
Salk scientists find that a vitamin D-derivative
makes tumors vulnerable to chemotherapy.
Sept. 25, 2014 - 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 isstill 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
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
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."
researchers on the study were Ruth T. Yu, Ning Ding, Annette R. Atkins,
Tiffany W. Tseng, Geoffrey M. Wahl, and Tony Hunter of the Salk
Institute for Biological Studies; Dannielle D. Engle, Herve Tiriac, and
David A. Tuveson of Cold Spring Harbor Laboratory; Eric A. Collisson of
the University of California, San Francisco; Frances Connor of Cancer
Research UK; Terry Van Dyke of NCI-Frederick; Serguei Kozlov and Philip
Martin of Leidos Biomed, Inc.; David W. Dawson and Timothy R. Donahue of
University of California, Los Angeles; Atsushi Masamune and Tooru
Shimosegawa of Tohooku University; Minoti V. Apte and Jeremy S. Wilson
of University of New South Wales; Beverly Ng, Sue Lynn Lau, and Jenny
Gunton of the Garvan Institute of Medical Research; Jeffrey A. Drebin
and Peter J. O'Dwyer of the University of Pennsylvania; and Christopher
Liddle of the University of Sydney.
work was supported by a Ruth L. Kirchstein National Research Service
Award, grants from the National Institutes of Health, the Leona M. and
Harry B. Helmsley Charitable Trust, the IPSEN Foundation, and the Samuel
Waxman Cancer Research Foundation. Additionally, individual researchers
receive funding from a Stand Up to Cancer Dream Team Translational
Cancer Research Grant, the Medical Research Council of Australia, the
Cancer Council of New South Wales, the Japan Society for the Promotion
of Science, the Howard Hughes Medical Institute and The Lustgarten
About the Salk Institute for Biological Studies:
Salk Institute for Biological Studies is one of the world's preeminent
basic research institutions, where internationally renowned faculty
probes fundamental life science questions in a unique, collaborative and
creative environment. Focused both on discovery and on mentoring future
generations of researchers, Salk scientists make groundbreaking
contributions to our understanding of cancer, aging, Alzheimer's,
diabetes and infectious diseases by studying neuroscience, genetics,
cell and plant biology, and related disciplines. Faculty achievements
have been recognized with numerous honors, including Nobel Prizes and
memberships in the National Academy of Sciences. Founded in 1960 by
polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent
nonprofit organization and architectural landmark.