June 1, 2001

MGH researchers have identified a special imaging technique that may allow doctors to determine whether certain experimental cancer drugs are actually working in patients. In a study published in this week's Nature Medicine, researchers for the first time used infrared fluorogenic imaging to measure the effectiveness of a class of drugs called protease inhibitors.

"This type of detection could mean several things," says lead author Christoph Bremer, MD, of the MGH Center for Molecular Imaging Research. "We'll have earlier cancer detection, because certain proteases are expressed before tumors are visible. We'll be better able to assess the aggressiveness of a tumor. And we'll be able to monitor new therapies that are developed to inhibit proteases."

Many different protease inhibitors currently are being tested in clinical trials. And until now, scientists had few means to monitor and measure effectiveness after they were administered.

"This imaging technique has been around for several years, but now we're using it for a new purpose," says Ching-Hsuan Tung, PhD, co-principal investigator with Ralph Weissleder, MD, PhD, both of the MGH Center for Molecular Imaging Research.

Proteases allow malignant cells to break through and invade healthy tissues. "Cancer needs some space. Proteases act like scissors and make space for the cancer," says Bremer. "They allow cancers to metastasize, and high levels of certain proteases indicate poor clinical outcomes for patients."

Although proteases also are crucial for the survival of healthy cells, several types are expressed in cancers at much higher levels than normal. Expression of these proteases has been linked to advanced tumor stage, invasiveness, metastasis and angiogenesis.

By generating a fluorescently labeled molecule that is activated by the protease's "scissoring," the scientists could sense protease activity in intact tumors in mice. When one of these molecules is cut, it fluoresces. "It's like turning on a light switch," explains Bremer.

The scientists then demonstrated that they could monitor protease inhibition within hours after administering Primostat, a protease inhibitor, which is currently in Phase III clinical trials. "Essentially, we found that the light is significantly less when this drug is given," says Bremer. In other words, he adds, the protease scissors cannot cut in the presence of the drug.