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By
Gila Z. Reckess
Jan.
3, 2005 — Drugs used to treat the tumors common in people
with a disorder called neurofibromatosis 1 rarely work,
and scientists now know why. The chemotherapy drugs
target a group of related proteins, call RAS proteins,
which are thought to be responsible for these tumors.
But researchers at Washington University School of Medicine
in St. Louis found that the disease affects only one
member of the protein family, and it happens to be the
one form of RAS that does not respond well to these
particular treatments.
The
study, which will appear in the Jan. 1 issue of the
journal Cancer Research, suggests where researchers
should now look for more promising approaches to treating
neurofibromatosis tumors, and may help scientists understand
other cancers related to RAS.
"The
downside is our study proves we're not using the right
therapies for this particular problem," says principal
investigator David H. Gutmann, M.D., Ph.D., the Donald
O. Schnuck Family Professor of Neurology and professor
of genetics and of pediatrics. "But there's a chance
to make lemonade out of this lemon: We now have a rational
reason for why these drugs aren't working, so we should
be able to explore new, more effective treatment options."
About
one in 4,000 newborns has neurofibromatosis 1, in which
every cell in the body has one normal and one mutated
copy of a gene called Nf1. If a cell's normal copy also
is mutated, tumors can form. Children with neurofibromatosis
1 are therefore predisposed to developing a variety
of serious complications as they grow older, including
skin, spine and brain cancers.
Scientists
previously found that RAS proteins become overly active
when both copies of the Nf1 gene are abnormal in tumors
from patients with neurofibromatosis 1. So physicians
have tried treating these tumors with drugs that prevent
RAS activity. Unfortunately, the results have been disappointing.
To
understand why, Gutmann's team examined whether all
forms of RAS are overly active in mouse cells lacking
both copies of the Nf1 gene. They specifically examined
support cells in the brain called astrocytes, which
often are affected by neurofibromatosis 1. Surprisingly,
only one member of the protein family, K-RAS, was significantly
affected, suggesting it is an important factor in this
disease.
Moreover,
when the team activated K-RAS in normal astrocytes,
the cells developed many of the same characteristics
and activities as those lacking Nf1. For example, both
types of abnormal astrocytes were round and dense, grew
and multiplied at a similar rate and moved around more
than normal. They also discovered they could reverse
abnormalities in cells without Nf1 by decreasing K-RAS
activity.
K-RAS
activation also mimicked Nf1 loss in live mice. Gutmann's
team previously discovered that mice without Nf1 genes
in their astrocytes grow an abnormally large number
of astrocytes in their brains, but they don't develop
tumors unless all other brain cells are missing at least
one copy of the gene. In this study, the researchers
found that K-RAS follows a similar pattern: When the
protein was overly active in astrocytes of mice with
two normal copies of Nf1, the cells multiplied but did
not develop into tumors; however, tumors did form when
K-RAS was activated in astrocytes of mice lacking one
copy of Nf1 in all cells.
Another
form of RAS previously suspected to be linked to neurofibromatosis,
called H-RAS, did not mimic loss of the Nf1 gene in
tissue culture or in live animals.
"Collectively,
these results suggest that K-RAS activation, specifically,
is the biological equivalent of Nf1 loss in astrocytes,"
Gutmann says. "If we can understand what K-RAS
does that's unique, we should be able to develop targeted
therapies."
The
research team already has made progress toward that
goal. Too much RAS and too little Nf1 are both known
to result in a cascade of events, including activation
of another protein called Rac1, which in turn activates
LIM kinase. Gutmann and his colleagues found that that
effect could be mimicked in normal astrocytes by selectively
activating K-RAS. Activating H-RAS did not trigger the
cascade.
"Though
K-RAS doesn't respond well to available chemotherapy
drugs, one of the proteins it interacts with might,"
Gutmann says. "By showing that K-RAS activates
a pathway that is unique from the pathways activated
by other RAS molecules, our findings may lead us to
a variety of better treatment targets."
Dasgupta
B, Li W, Perry A, Gutmann DH. Glioma formation in neurofibromatosis
1 reflects preferential activation of K-RAS in astrocytes.
Cancer Research, Jan. 1, 2004.
Funding
from the National Institutes of Health and the United
States Department of Defense supported this research.
Washington
University School of Medicine's full-time and volunteer
faculty physicians also are the medical staff of Barnes-Jewish
and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked
second in the nation by U.S. News & World Report.
Through its affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of Medicine is
linked to BJC HealthCare.
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