September 15, 2004
Decoupling the Control of Brain
to Find Better Treatments
(Philadelphia, PA) - When he’s not in the operating
room performing surgery, Donald M. O’Rourke,
MD, Associate Professor of Neurosurgery at
the University of Pennsylvania School of Medicine
is fighting brain tumors from the research laboratory
bench. He and colleagues are making inroads to understanding
the basic molecular biology that makes brain tumors
so hard to treat. An estimated 41,000 new cases of primary
brain tumors are expected to be diagnosed in 2004, according
to the American Brain Tumor Association.
Most recently, O’Rourke and Gurpreet S.
Kapoor, PhD, Research Associate in O’Rourke’s
laboratory, have discovered that two proteins sitting
on the surface of cells are the interconnected switches
for turning uncontrolled cell growth on or off in the
brain and other tissues. These coupled proteins are
the Epidermal Growth Factor Receptor (EGFR) and the
Signal Regulatory Proteina1
(SIRPa1). They report their
findings in the September 15 issue of Cancer Research.
In past work, O’Rourke and colleagues found that
if EGFR was activated, cancer cells tended to survive
longer and migrate to unaffected parts of the brain
to spread the cancer. In over 50 percent of glioblastomas
- one type of brain cancer that is the leading cause
of cancer-related deaths in males aged 20-39 - too much
EGFR is produced. In other glioblastomas, too much of
a variant called EGFRvIII is also produced, which is
linked to poor survival and resistance to treatment
in some brain-cancer patients.
“Most of my translational efforts are targeted
at this variant form of EGFR since no treatments are
out there for glioblastomas,” says O’Rourke.
“We believe that development of malignancy in
the brain is not simply related to cell division; it’s
a combined process that involves cell division, cell
survival, cell migration and movement, and ultimately
angiogenesis - the building of new blood vessels in
tumors.” All four of these processes occur at
the same time. Many of the conventional chemotherapies
for brain tumors are directed at stopping cell division,
which makes these therapies not completely successful.
Using human glioblastoma cells, they found that when
another protein called SHP-2 is bound to EGFR, the cell
goes into an overactive state, resulting in cancerous
growth. However, when SHP-2 is bound to SIRPa1, uncontrolled
cell growth is stopped. “This is probably the
normal state for a brain cell,” says O’Rourke.
O’Rourke showed in earlier work that when SIRPa1
is activated in cancer cells it can inhibit cell growth
and eventually kill them. In the present study, though,
O’Rourke and Kapoor demonstrate that when EGFR
is turned on, the genetic machinery to produce SIRPa1
is shut down, effectively bypassing the cell’s
natural ability to control unchecked growth. Another
way a cancer cell circumvents the brakes on reproducing
is to sequester SHP-2 away from SIRPa1, so the cell
keeps on dividing.
Many of the newer cancer therapies inhibit EGFR activation,
which is an indirect way of treating cancer. Stimulating
SIRPa1 may be a more direct way to stop cancer because
that receptor is a naturally occurring way that the
body inhibits cancerous growth. “We may then have
a greater chance at beating brain cancer than by inhibiting
EGFR in a cell that already has an abundance of EGFR
in it,” says O’Rourke. Future efforts by
O’Rourke’s laboratory will be directed at
finding combinations of inhibitors that block brain
cancer cell migration, which will make all local therapies
- including surgery - more effective by confining the
cancer to a particular location.
This research was funded by the National Institutes
of Health, the Department of Veterans Affairs, and The
Brain Tumor Society.
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