A two-fisted punch against cancer metastasis

Almost 20 years ago, a class of cancer drugs called MMP inhibitors failed miserably in human trials despite looking like cure-alls in mouse models of metastatic cancer. Now researchers at Duke University say they’ve figured out why the drugs didn’t work. They believe their discovery could lead to new ideas for combination treatments against metastatic cancer.

MMPs (matrix metalloproteinases) are enzymes that dissolve the outer membranes of cells. These enzymes have long been believed to be vital for allowing cancer cells to escape their point of origin and then invade healthy tissues elsewhere in the body. So the oncology community was flummoxed when molecules designed to inhibit MMPs were unable to stop cancer from spreading in human trials.

By studying C. elegans worms, the Duke team discovered that invasive cells can survive and spread without MMPs. They do so by building a “battering ram”—a protrusion that busts its way in and out of cell walls. They published their findings in the journal Developmental Cell.

A team led by Duke biology professor David Sherwood, Ph.D., observed cell behavior in both normal worms and worms that were genetically modified to lack MMP enzymes. That’s when they discovered the protrusion that developed in the absence of MMP.

In normal worms, invading cells moved through a narrow opening "kind of like the escape tunnel in 'The Shawshank Redemption,'" Sherwood said in a statement. "But in knockout worms it's more like the Kool-Aid Man when he busts through walls."

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The Duke researchers went on to develop a way of preventing the invasive cells from getting through walls. They found that the protrusion contains stiff filaments and is able to recruit mitochondria—the energy centers in cells—to power their attack. So they figured out a way to inhibit a mitochondrial gene. That prevented invading cells from bashing through other cells’ walls.

Despite the early failures of MMP inhibitors, oncology researchers are still interested in finding new ways to block the enzymes and stop cancer metastasis. Researchers at the University of California at Riverside developed antibodies that specifically bind to abnormal MMPs, and preclinical studies indicated they might be more effective at preventing the spread of cancer than the first generation of MMP inhibitors, which were more broad-based.

Gilead suffered a failure of an MMP inhibitor called andecaliximab in ulcerative colitis. But it continues to test the compound in combination with Bristol-Myers Squibb’s immuno-oncology blockbuster Opdivo in gastric cancer.

The Duke researchers believe their findings could inspire new ideas for combination treatments encompassing MMP inhibitors. Blocking both MMPs and the battering rams cells build when the enzymes are depleted could keep cancer from spreading, they said.