Enzyme's role in cancer's ability to spread scrutinized
Lynn Matrisian, Ph.D. (center), is investigating ways to curb cancer's ability to spread. Here she works with graduate students Rebecca Ann Wagenaar (left) and Tracy Christine Vargo. (Photo by Donna Marie Jones).
When Lynn M. Matrisian, Ph.D., was training in Strasbourg, France, more than a decade ago, she cloned the gene for an enzyme that breaks down protein barriers between cells.
Matrisian, professor of Cell Biology at Vanderbilt University Medical Center, was studying rat cells in plastic dishes at the time. Twelve years later, new drugs that inhibit that family of enzymes are being studied at the Vanderbilt Cancer Center and other medical centers to determine whether they can hold tumors in check.
"I'm excited that it's gone this far," said Matrisian, who is also associate director for Education and Training at the VCC. "I feel that I had a part in this whole puzzle."
These enzymes are called matrix-degrading metalloproteinases. The "metal" portion of the word refers to their need to use a metallic ion to do their work in the body.
Their potential role in cancer is not clearly understood, but it is believed that by breaking down the protein barriers between cells, they enable tumor cells to get into the blood stream and spread to other parts of the body, Matrisian said.
"These enzymes are not widely expressed in normal tissues," she said. "They come on in very specific cases, such as during wound healing or at certain points in the menstrual cycle, but they come on like gang-busters in a lot of cancers."
Pharmaceutical companies have now synthesized drugs that inhibit the action of these enzymes. The drugs have been tested in phase 1 safety trials.
In December, the VCC and 13 Tennessee, Kentucky and Alabama hospitals in its affiliate network began enrolling patients in a Phase III study of a drug called marimastat, one of these metalloproteinase inhibitors.
The international, multi-center trial, sponsored by the drug's manufacturer, is investigating marimastat in patients with small-cell lung cancer who are in remission, said Dr. Russell F. DeVore, assistant professor of Medicine, the study's prinicipal investigator.
"The Vanderbilt Cancer Center Affiliate Network has been the top accruer in the world for this trial. The question is whether marimastat will extend remission and thus extend lives and possibly even prevent recurrence," he said. "It's a very exciting and important trial."
Results from previous basic science and clinical work suggest that inhibiting the action of these enzymes can keep a tumor from growing and spreading. The precise mechanism is not known ‹ it could be that the enzymes in essence make room for the tumor to grow or are needed for new blood vessels, essential for tumors to spread, Matrisian said.
But simply stopping the tumor in its tracks might be enough, she and DeVore said.
"If the tumor could be kept in check, a patient could live with that," DeVore said.
So far, more than a dozen patients have been enrolled in the marimastat trial through the affiliate network, DeVore said.
The VCC will also soon begin enrolling patients in the first phase I study of another metalloproteinase inhibitor called AG3440. Dr. Kenneth R. Hande, professor of Medicine and Pharmacology, will be the principal investigator, and DeVore will be co-investigator.
"This study will be the first to test this particular metalloproteinase inhibitor in patients with cancer," Hande said. "It has been selected for development with the goal of more specifically targeting enzymes from cancer cells and avoiding the metalloproteinase enzymes formed to maintain the normal function of joints."
The AG3440 study, which opened July 1, will attempt to determine the optimal and safe daily dose of this drug, any toxicities and whether it is active against any particular cancer, Hande said. It will be open to qualifying patients for whom other treatments have failed and for whom no known effective therapy is available.
Meanwhile, Matrisian and her colleagues continue to study metalloproteinases in the laboratory with the goal of better understanding their action and making discoveries to help fine-tune the drugs.
"For example, one of the side effects of marimastat has been to cause pain in the patient's writing hand, and I'd love to be able to figure out why that's happening," Matrisian said.
"The idea is to use a genetic approach in animal studies to get more specific. That way, you could design the drug to avoid side effects and make it more specific to certain cancers."