Taking the blinders off  pg. 2

In a mouse model of breast cancer, for example, Vanderbilt researchers have shown that the level of several proteins plummeted within 12 hours after administration of Tarceva, a cancer drug that blocks the receptor for epidermal growth factor. This suggests that the proteins may be “biomarkers” for tumor growth.

“You could see these changes… way before any surgical or MRI (magnetic resonance images) will show you there is tumor shrinkage,” says Richard Caprioli, Ph.D., director of the Mass Spectrometry Research Center, who participated in the research.

More study is needed to determine whether a drop in the concentration of these proteins can be reliably correlated with tumor shrinkage in response to Tarceva. With the help of proteomics in the future, however, “we might be able to predict if a drug is going to be effective in a patient—even after the first dose,” Caprioli says.

Watching drugs work

Imaging technologies offer another avenue for predicting the effectiveness of drug therapy.

Researchers in the Vanderbilt University Institute of Imaging Science are exploring dynamic contrast imaging, an MRI method that can create a three-dimensional image of angiogenesis, new blood vessel formation. When standardized, this method may provide a way to determine the effectiveness of anti-angiogenic agents, says institute director John Gore, Ph.D.

Vanderbilt recently installed a 7 Tesla magnet, 140,000 times the strength of the Earth’s magnetic field, which will allow institute researchers to conduct magnetic resonance spectroscopy.

Using this technique, researchers can measure very precisely the levels of neurotransmitters in the brain. “We think that’s an important area,” Gore says, “not only for certain brain disorders such as addiction, but also for looking at the effects of drugs.”

Positron emission tomography or PET is another imaging technology that is being harnessed for drug discovery. By tacking a radioisotope of fluoride or carbon onto a drug, for example, researchers can use PET to detect the radiation emitted by the labeled drug, and create an image of where it goes in the body.

Fluorescence imaging techniques, such as two-photon excitation microscopy, potentially provide a way to look into the living cell and watch what happens when a drug hits its target. This not only may aid drug discovery; it may salvage a promising class of cancer drugs called MMP inhibitors that were largely abandoned by drug companies after several clinical trials failed to show any survival benefit in patients with advanced disease.

MMP stands for matrix metalloproteinases, enzymes that are thought to contribute to metastasis, the major cause of cancer deaths, by helping to increase the tumor’s blood supply and means of escape to other parts of the body.

Vanderbilt cancer researchers have developed a “proteolytic beacon” that can detect and measure MMP activity. The beacon is a fluorescent probe that releases a flash of fluorescence when split by the enzyme.

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