In the hunt for new
cancer drug targets, scientists from the
Johns Hopkins Kimmel 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, 2004 issue of
Science, reveals more options for creating personalized therapies tailored to counteract mutated
gene pathways present in individual tumors.
"What makes this discovery significant is that we've found mutations that directly affect cancer development," says Victor Velculescu, M.D., Ph.D., 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' 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, which plays an opposite role, turning a pathway on and accelerating cellular events.
"If a bus' brakes are broken and they can't be fixed, another way to slow it down is to let up on the accelerator," explains Velculescu. "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, Ph.D., postdoctoral fellow and first author of the paper.