Decoupling the Control of Brain Cancer Cells 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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