Customized virus kills brain tumor stem cells that drive lethal cancer
HOUSTON - A tailored virus destroys brain tumor stem cells that
resist other therapies and cause lethal re-growth of cancer after
surgery, a research team led by scientists at The University of Texas
M. D. Anderson Cancer Center reports in the Sept. 18 edition of the
Journal of the National Cancer Institute.
"We have shown first in lab experiments and then in stem cell-derived
human brain cancer in mice, that we have a tool that can target and
eliminate the cells that drive brain tumors," says co-senior author
Juan Fueyo, M.D., associate professor in M. D. Anderson's Department
of Neuro-Oncology. A request to launch a clinical trial of the virus,
called Delta-24-RGD, is expected to go to federal regulators this
month.
The virus was tested against the most aggressive brain tumor -
glioblastoma multiforme, which originates in the glial cells that
surround and support neurons. It is highly resistant to radiation and
chemotherapy and so invasive that surgery almost never eliminates it.
Patients suffering from this malignant glioma live on average for
about 14 months with treatment.
Fueyo and colleagues developed Delta-24-RGD to prey on a molecular
weakness in tumors and altered the virus so it could not replicate in
normal tissue. They showed in a JNCI paper in 2003 that the virus
eliminated brain tumors in 60 percent of mice who received injections
directly into their tumors. The virus spreads in a wave through the
tumors until there are no cancer cells left, then it dies.
Since 2004 scientists have found that brain tumors are driven by
haywire stem cells that replicate themselves, differentiate into
other types of cells, and bear protein markers like normal stem cells.
"Research has shown that these cancer stem cells are the origin of
the tumor, that they resist the chemotherapy and radiation that we
give to our patients, and that they drive the renewed growth of the
tumor after surgery," Fueyo said. "So we decided to test Delta-24-RGD
against glioma stem cells and tumors grown from them."
The research team led by Fueyo, co-senior author Frederick Lang,
M.D., professor in M. D. Anderson's Department of Neurosurgery, and
first author Hong Jiang, Ph.D., instructor in neuro-oncology, derived
four brain tumor stem cell lines from four specimens of glioblastoma
multiforme. All four lines exhibited the characteristics and protein
signatures of stem cells. Delta-24 succeeded in killing all four
types in the lab.
Next, the researchers grafted the stem cell lines into the brains of
mice and treated the resultant tumors with injections of Delta-24-
RGD. Untreated mice had a mean survival time of 38.5 days, while
treated mice had a mean survival of 66 days. Two of the eight treated
mice survived for 92 days, until the end of the experiment, with no
neurological symptoms.
"It's important in animal models to see improvement in survival in
the majority of animals, but to have some be cured and survive a long
time without neurological symptoms is very rare," Fueyo said. "We
have to be cautious, because an animal model doesn't fully represent
humans, but the tumors grown by these stem cells closely resemble the
tumors we see in our patients, which is an exciting finding in
itself."
Tumors in other mouse models tend to be round and self-contained,
explains co-senior author and Frederick Lang, M.D., professor in M.
D. Anderson's Department of Neurosurgery. Malignant tumors in
patients are never round, they invade other tissues and delve deeply
into the brain. The cancer stem cell-derived tumors in these
experiments have the irregular shape and invasive characteristics of
their human counterparts.
"That similarity to the human tumor is encouraging,
it's also encouraging that we got basically the same results with
Delta-24-RGD in this experiment that we got in our earlier experiment
using other tumor models."
A clinical quality version of Delta-24-RGD has been manufactured by
the National Cancer Institute and an independent consultant has
completed a toxicology assessment. An Investigational New Drug
Application to proceed with a phase I clinical trial is expected to
be filed with the U.S. Food and Drug Administration in September. A
clinical trial could began as early as this fall.
Delta-24-RGD exploits the fact that a protein called retinoblastoma
(Rb) is either missing or defective in brain tumors. Rb normally
guards against both the proliferation of cancerous cells and against
viral infection. So the virus has an easier time invading tumors and
replicating in its cells. Adenoviruses attacking normal cells employ
their own protein, E1A, to counteract retinoblastoma'
measures. To keep Delta-24-RGD out of normal cells, Fueyo and
colleagues deleted a small part of the gene that produces E1A.
The JNCI paper shows that Delta-24-RGD forces tumor cells to devour
themselves until they die. This self-cannibalizatio
autophagy, occurs when a cell forms a membrane around part of its
cytoplasm or an organelle and then digests the contents, leaving a
cavity. A cell that dies from autophagy is riddled with cavities.
Cells normally employ autophagy temporarily to survive when nutrients
are short, to recycle components to form new organelles, or to fend
off viral or bacterial infection. In cancer research, there is
evidence both that autophagy is a form of programmed cell death
triggered to prevent the replication of damaged cells and that cancer
cells in some instances employ it to survive attack.
"Our next experiments will address whether the cell kills itself or
dies defending itself against the virus," Fueyo says. Sure, the cell
dies either way, but the distinction is important, Fueyo says,
because the virus could be redesigned to either fuel or block
autophagy to make it more effective. The autophagic protein Atg5 is
heavily expressed in the dead tumor cells, making it a potential
biomarker of the virus' effectiveness.
###
The National Cancer Institute funded this research.
Co-authors with Fueyo, Lang and Jiang are Candelari Gomez-Manzano,
Hiroshi Aoki, Marta Alonso, Seiji Kondo, Jing Xu, Yasuku Kondo, and
Howard Colman, all of the M. D. Anderson Brain Tumor Center; B.
Nebiyou Bekele, of M. D. Anderson's Department of Biostatistics; and
Frank McCormick, Cancer Research Institute and Comprehensive Cancer
Center, University of California, San Francisco. Aoki also is
affiliated with the Department of Neurosurgery, Brain Research
Institute, Niigata University in Niigata, Japan.
EMBARGOED FOR RELEASE UNTIL 4 P.M. EDT, TUESDAY, SEPTEMBER 11, 2007
Public release date: 11-Sep-2007
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Contact: Scott Merville
sdmervil@mdanderson
713-792-0661
University of Texas M. D. Anderson Cancer Center
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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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