A drug that shuts down a critical cell signaling
pathway in the most common and aggressive type
of adult brain cancer successfully kills cancer stem cells
thought to fuel tumor growth and help
cancers evade drug and radiation therapy, a Johns Hopkins
study shows.
In a series of laboratory and animal experiments,
Johns Hopkins scientists blocked the signaling
system, known as Hedgehog, with an experimental compound
called cyclopamine to explore the
blockade's effect on cancer stem cells that populate
glioblastoma multiforme. Cyclopamine has long
been known to inhibit Hedgehog signaling.
The scientists reported their findings in the journal
Stem Cells published online July 19.
"Our study lends evidence to the idea that the lack of
effective therapies for glioblastoma may
be due to the survival of a rare population of cancer stem
cells that appear immune to conventional
radiation and chemotherapy," said Charles G. Eberhart,
associate professor of pathology,
ophthalmology and
oncology in the School of Medicine, who led the work.
"Hedgehog inhibition kills
these cancer stem cells and prevents cancer from growing,
and may thus develop into the first stem
cell-directed therapy for glioblastoma."
Eberhart cautioned that while his study appears to
prove the principle of Hedgehog blocking,
much work remains before cyclopamine or any similar drug
can be tested in patients. Scientists must
determine whether the drug can be effectively and safely
delivered to the whole body or whether it
must go into the brain, and what, if any, adverse impact on
normal stem cells the treatment might
cause.
The new study adds to the growing evidence that only a
small percentage of cancer cells — in this
case, stem cells — are capable of unlimited
self-renewal and that these cells alone power a tumor's
growth.
Eberhart focused on two pathways important to the
survival of normal brain stem cells,
Hedgehog and Notch, suspecting that brain cancer stem cells
cannot live without them.
The Hedgehog gene plays a major role in controlling
normal fetal and postnatal development and,
later in life, in helping normal adult stem cells function
and proliferate.
The Johns Hopkins scientists first tested 19 human
glioblastomas, removed during surgery and
frozen immediately, and found Hedgehog active in five at
the time of tumor removal. They also found
Hedgehog activity in four of seven glioblastoma cell
lines.
Next, the team used cyclopamine, chemically extracted
from corn lilies that grow in the Rocky
Mountains, to inhibit Hedgehog in cell lines growing on
plastic or as neurospheres, round clusters of
stem cells that float in liquid nutrients. This reduced
tumor growth in the cell-laden plastic by 40
percent to 60 percent and caused the neurospheres to fall
apart without any new growth of the cell
clusters.
The researchers also pre-treated mice with cyclopamine
before injecting human glioblastoma
cells into their brains, resulting in cancer cells that
failed to form tumors in the mice.
Other researchers have shown that radiotherapy fails
to kill all cancer stem cells in
glioblastomas, apparently because many of these cells can
repair the DNA damage inflicted by
radiation. The Johns Hopkins team suggests that blocking
the Hedgehog pathway with cyclopamine
kills these radiation-resistant cancer stem cells.
In previous laboratory experiments, Eberhart used
cyclopamine to block Hedgehog using
medulloblastoma cells, the most common brain cancer
occurring in children.
Along with childhood brain cancers, cyclopamine has
shown early promise in treating skin cancer;
rhabdomyosarcoma, a muscle tumor; and multiple myeloma, a
cancer of the white blood cells in bone
marrow.
"What excites me is that we have taken things we
learned about Hedgehog signaling in these
relatively rare childhood brain tumors and translated them
into an even more aggressive adult tumor,"
Eberhart said.
More than 10,000 Americans die annually from
glioblastomas. Radiation is the standard therapy
for the disease, and several years ago the U.S. Food and
Drug Administration approved adding the
drug temozolomide to radiotherapy because the combination
provided a small survival increase.
First author Eli E. Bar, a postdoctoral fellow, said,
"This is an incredibly difficult tumor to
treat. Survival for glioblastoma has not changed much in 30
years. With the addition of temozolomide,
survival got bumped from 12 months to 14 or 15 months."
This study was funded by the nonprofit Brain Tumors
Funders' Collaborative, which is supported
by eight private philanthropic and advocacy
organizations.
Additional authors are Aneeka Chaudhry, Alex Lin, Xing
Fan, Karisa Schreck, William Matsui and
Alessandro Olivi, all of Johns Hopkins; and Angelo L.
Vescovi, of the University of Milan Bicocca, and
Francesco DeMeco, of the Istituto Nazionale Neurologico
Carlo Besta, both in Milan, Italy.
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