Tumor Suppressor Gene Family May Be Key to New Colon
By Vanessa Wasta
Johns Hopkins Medicine
In the hunt for new cancer drug targets, scientists
from the Johns Hopkins
Cancer Center and the Howard Hughes Medical Institute
have discovered mutations in a family of genes linked to
more than a quarter of colon cancers, as well as several
other common cancers including breast and lung. Their
research, published in the May 21 issue of Science,
reveals more options for creating personalized therapies
tailored to counteract mutated gene pathways present in
"What makes this discovery significant is that we've
found mutations that directly affect cancer development,"
says Victor Velculescu, senior author of the study and
assistant professor at the Johns Hopkins Kimmel Cancer
Center. "Most gene discoveries today focus on finding
increased or decreased activity of a gene that may not
affect cancer progression, akin to passengers on a bus that
can't control the bus's speed or direction. What we've
found are the brakes of the bus."
After analyzing 157 colon cancers, the research team
found 77 mutations in six genes that make tyrosine
phosphatases, enzymes that help coordinate signals that
manage cellular growth, death, differentiation and nearby
tissue invasion. They normally work by turning off tumor
growth, as so-called tumor suppressors, but in cancers
these genes are mutated and no longer work properly.
Because it is difficult to restore a mutated suppressor
gene with cancer drugs, the investigators believe
phosphatases themselves are not good drug targets. Yet for
every tyrosine phosphatase there is a matching enzyme,
called a tyrosine kinase, that plays an opposite role,
turning a pathway on and accelerating cellular events.
"If a bus's brakes are broken and they can't be fixed,
another way to slow it down is to let up on the
accelerator," Velculescu explains. "In this case, the
faulty brakes are mutated tyrosine phosphatases, and the
accelerators are the tyrosine kinases." Tyrosine kinases
have been of critical value in the success of such
cancer-fighting drugs as Gleevec, Iressa and Herceptin,
which block proteins made by tyrosine kinase genes.
Last May, Velculescu's team systematically analyzed
tyrosine kinases and found mutations in this family of
genes linked to more than 30 percent of colon cancer. "We
will be conducting additional research to explore tyrosine
phosphatase pathways and match them up with corresponding
kinases in order to find targets for potential inhibitory
drugs," says Zhenghe Wang, postdoctoral fellow and first
author of the paper.
More than two-thirds of colon cancers have mutations
in the tyrosine kinase and phosphatase families, as well as
another kinase gene Velculescu's group identified recently.
Tyrosine phosphatase mutations also were found in two of 11
(18 percent) lung cancers, two of 12 (17 percent) gastric
cancers and one of 11 (9 percent) breast cancers.
Colon cancer strikes 147,500 Americans every year, and
57,100 will die from the disease. This research was funded
by the Ludwig Trust, the Maryland Cigarette Restitution
Fund, the Benjamin Baker Scholarship Fund, the Clayton Fund
and the National Institutes of Health.
In addition to Velculescu and Wang, the following
scientists from the Johns Hopkins Kimmel Cancer Center and
Howard Hughes Medical Institute participated in this
research: Dong Shen, D. Williams Parsons, Alberto Bardelli,
Jason Sager, Steve Szabo, Janine Ptak, Natalie Silliman,
Brock A. Peters, Michiel S. van der Heijden, Giovanni
Parmigiani, Tian-Li Wang, Greg Riggins, Kenneth W. Kinzler
and Bert Vogelstein.
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