Hopkins researchers identify key pathway in colon cancer Scientists hope discovery will lead to drugs to target chemicals causing disease


Scientists at the Johns Hopkins Oncology Center and colleagues in the Netherlands say they have identified one of the key chemical pathways behind the development of colon cancer, the second leading cancer killer in the United States.

The researchers say the pathway is the "initiating event" in a long series of changes that cause cells to grow out of control, forming pre-cancerous polyps and finally malignant tumors.

Besides giving scientists a better understanding of how the cancers develop, the scientists hope the discovery will lead to long-sought drugs that would specifically target the chemicals that give rise to cancer. These would be preferable to current drugs, which are hard to tolerate because they destroy healthy cells along with unhealthy ones.

"In a sense, this is a defining pathway that is important in the early stages of colon cancer," said Dr. Curtis C. Harris, who heads the laboratory of human carcinogenesis at the National Cancer Institute in Bethesda. "There are still missing pieces of the pathway, but now they and others know where to search."

Each year, about 130,000 cases of colon cancer are diagnosed in the United States, making it the fourth most common cancer behind prostate, breast and lung. It trails only lung cancer in lethality, killing 55,000 people each year.

The new finding, reported in this week's edition of the journal Science, builds upon the 1991 discovery by scientists at Hopkins and the University of Utah of the APC tumor suppressor gene, a built-in mechanism for quashing tumors before they spiral out of control. People who inherit defective copies or acquire mutations during their lifetimes run a high cancer risk.

Better understanding

Until now, however, scientists lacked a good understanding of how the mutations led to cancer.

After studying hundreds of colon tumors, researchers at Hopkins and University Hospital in Utrecht recognized that the healthy APC gene works by "turning down" two other genes that produce harmful chemicals, the B-catenin and Tcf proteins. These proteins, when produced in abnormally large quantities, interfere with mechanisms that tell a cell when to reproduce and when to die.

A tumor is a proliferation of cells that, simply put, do not know when to die.

Dr. Kenneth Kinzler, lead author of the report, said 85 percent of colon cancers are triggered by defective APC genes. A smaller fraction are triggered by mutant genes that produce B-catenin. In either case, tumors develop because the normal process of "programmed cell death" is turned off.

"From the basic science point of view, we now have a good feel for how the major tumor suppressor gene for colon cancer operates," Kinzler said. "In the future, it provides a target for the development of drugs for the treatment of colon cancer."

One of the chief goals of cancer research is the development of "rational drugs" that attack the specific chemicals responsible for cancer. In theory, they would be more effective and cause fewer side effects than drugs now used in cancer chemotherapy.

There aren't any rational cancer drugs now in use, although many are being investigated. Harris noted that drugs generally take 10 to 20 years to develop and that there is no reason to believe that drugs based on a new strategy of cancer control should arrive any faster.

"As we better understand the processes, we will be able to focus our attention and energies and hopefully drugs on specific parts of these pathways and on specific gene products," Harris said.

"This is a very stellar group of cancer researchers," he said of the Hopkins group led by Kinzler and Dr. Bert Vogelstein. "They are putting one block at a time into our current understanding of how cancer is formed."

For more than a decade, the Hopkins team has unraveled the process by which colon tumors are triggered by a series of gene mutations in a single cell. "It probably takes seven to 10 mutations for colon cancer to develop," Kinzler said. "These are the earliest, the initiating mutations."

In another article appearing in Science, a researcher from Onyx Pharmaceuticals in Richmond, Calif., said the beta-catenin process is implicated in almost a third of all cases of melanoma, a dangerous form of skin cancer.

Scientists will now want to know if the same pathway is implicated in other cancers, Harris said.

Pub Date: 3/22/97

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