[Editors] MIT IDs link between brain tumor proteins

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
http://web.mit.edu/newsoffice/www

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MIT IDs link between brain tumor proteins

--Work could guide drugs for especially aggressive cancer
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For Immediate Release
THURSDAY, JULY 19, 2007
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

CAMBRIDGE, Mass.--MIT researchers have identified a critical link 
between two proteins found in brain tumors, a discovery that could 
eventually help treat a form of brain cancer that kills 99 percent of 
patients.

Glioblastoma multiforme (GBM), the most aggressive brain tumor in 
adults, strikes about 15,000 people in the United States each year. 
GBM is currently treated with a combination of surgery, radiation and 
chemotherapy, but those treatments have proven ineffective. Most 
patients die within a year.

Now, MIT scientists have uncovered a connection between two proteins 
found in the tumor cells, and they have demonstrated that attacking 
both of those proteins kills tumor cells much more effectively than 
targeting either one alone.

The researchers, led by Forest White, MIT associate professor of 
biological engineering, report their findings in the early online 
edition of the Proceedings of the National Academy of Sciences for 
the week of July 16-20.

Their work could guide drug developers seeking treatments for GBM, 
which has proven resistant to all drugs that have been tried against 
it.

The team focused on a protein called EGFRvIII, a mutated form of the 
cell receptor for epidermal growth factor (EGF). The mutated 
receptor, which is found in approximately a quarter of GBM tumors, is 
continuously active and relentlessly pushes cells to keep growing and 
dividing.

Doctors have tried treating GBM patients with drugs that inhibit 
EGFRvIII, but they have had little effect. This could be because the 
continuous stimulation of the receptor is so intense and because the 
receptor interacts with numerous other proteins that also promote 
tumor growth, said White, who is also affiliated with MIT's Center 
for Cancer Research and its Computational and Systems Biology 
Initiative.

The researchers believe it is the cumulative action of EGFRvIII and 
those other proteins that leads to tumor growth.

"It seems that it is not the activation of one receptor that results 
in   cancer. It's the action of multiple receptors that leads to the 
tumors we see," said Paul Huang, a graduate student in biological 
engineering and lead author of the paper. "A potential way to 
overcome this is to attack multiple targets instead of just one."

To find out what other proteins are involved in tumor growth, the 
researchers used a tool known as mass spectrometry to analyze the 
network of proteins activated by EGFRvIII in GBM tumor cells.

They found that when EGFRvIII is activated, so is another receptor 
called c-Met. C-Met is normally active during human development, but 
it's turned off in most adult cells.

Until now, there had been no evidence of any "cross-talk" between 
c-Met and EGFRvIII in GBM. This discovery could offer an explanation 
for why GBM tumors are so invasive, because over-activated c-Met has 
already been implicated in very invasive types of lung and breast 
cancers.

The researchers don't know yet how EGFRvIII is activating c-Met, and 
whether other proteins are involved  in the activation.

"The mechanism underlying this control has yet to be fully 
characterized," said White. "Our data shows that as EGFRvIII is 
activated, c-Met is activated as well. Whether it's direct, or 
indirect, is something that we are currently deciphering."

The new knowledge of c-Met's involvement could give researchers a 
potent tool to attack GBM tumors. When the MIT group treated tumor 
cells with drugs that inhibit EGFRvIII and c-Met, respectively, much 
lower doses were required to kill the cells than when either drug was 
given alone.

There are several EGFRvIII inhibitors in clinical trials now, and 
some have already been approved to treat other cancers. Drug 
companies are also working on c-Met inhibitors, and Huang estimated 
that some might be available in five to 10 years.

Other MIT authors on the paper are Ryan Flynn, a sophomore biology 
major, and Zachary Brewer, a senior chemical engineering major. This 
work was performed in collaboration with researchers at the Ludwig 
Institute of Cancer Research (San Diego Branch) led by Webster 
Cavenee and Frank Furnari.  The research was funded by the National 
Cancer Institute, the National Institutes of Health and the Goldhirsh 
Foundation.

--MIT--

Written by Anne Trafton, MIT News Office