Experimental anti-cancer drug made from corn lillies kills brain
tumor stem cells
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.
They reported their findings in the journal Stem Cells published
online on 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,
associate professor of pathology, ophthalmology and oncology, 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.
"Once you've answered those questions in animals, the next step would
be starting phase I clinical trials in humans," Eberhart said.
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, first studied in fruit flies, got its name because
during embryonic development, the mutated version causes flies to
resemble a spiky hedgehog. The pathway plays a major role in
controlling normal fetal and postnatal development, and, later in
life, 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 cells
lines growing on plastic or as neurospheres, round clusters of stems
cells that float in liquid nutrients. This reduced tumor growth in
the cell-laden plastic by 40 to 60 percent, and caused the
neurospheres to fall apart without any new growth of the cell
clusters.
The researchers also pretreated 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 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.
"This is an incredibly difficult tumor to treat," says first author
Eli E. Bar, Ph.D., a postdoctoral fellow. "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 from Johns Hopkins;
Angelo L. Vescovi of the University of Milan Bicocca in Milan, Italy;
and Francesco DeMeco of the Istituto Nazionale Neurologico "Carlo
Besta" in Milan.
Public release date: 30-Aug-2007
Contact: Vanessa Wasta
wastava@jhmi.
410-955-1287
Johns Hopkins Medical Institutions
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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