Tiny molecules have big potential as cancer drugs, Stanford researcher believes


PHILADELPHIA Many cancer therapies take a "big stick" approach, targeting rapidly dividing cells in the body to stop malignancies in their tracks but often triggering horrible side effects in the process. New research from the Stanford University School of Medicine points toward the possibility of a different type of cancer drug small molecules that would home in on the proteins tumors need without poisoning patients.

Matthew Bogyo, PhD, assistant professor of pathology, will discuss his studies of some of these molecules at an Aug. 24 talk during the "Genomic Approaches to Enzymology" session of the American Chemical Society's national meeting in Philadelphia.

Previous studies have shown that an increase of certain proteins, called cathepsin cysteine proteases, is associated with tumor development. "People have shown that more of the cathepsins are present in cancers and that they appear to be secreted by cancer cells," said Bogyo. "The question is what are they doing and does it help to block them?" To find out, Bogyo and colleagues used fluorescent tags to track cathepsin activity in mouse models of two types of cancer. They found the cathepsins helped build blood vessels to the tumors as well as increase tumor growth and invasiveness.

The team also tried giving a broad-spectrum cathepsin inhibitor to some cancerous mice and found that it slowed tumor development both in early and late stages of growth with no apparent side effects. The National Cancer Institute has since fast-tracked the inhibitor into studies of toxicity and pharmacodynamics as a potential drug. Meanwhile the research group has used the compound as a jumping-off point, testing similar compounds to find those that bind specifically to "problem" cathepsins, instead of to all of them. Bogyo is also looking for additional molecules that have better potency and pharmacodynamic properties.

Bogyo will give details on tests of some of these molecules at his presentation. If one of the molecules turns out to vanquish tumors but not their hosts, it could become one of the first drugs of its kind, he said. "Most cancer drugs are very toxic," he said. "There are very few rationally designed oncology drugs in use today that are made with a specific target in mind."

Designing an inhibitor requires knowing which protein to inhibit and what the protein does. Finding out the latter is a particularly difficult task in the case of cathepsins because of the nature of proteases, Bogyo said. "Proteases take other proteins and degrade them into little bits, and so it's hard to figure out what those proteins were doing," he said. "We're beginning by focusing on individual proteases, seeing what happens when you shut down a specific member of that family. And I think we're going to find that some of those proteases are more important than others for promoting things like tumor growth and angiogenesis."

The implications of finding the right inhibitor would reach far, Bogyo said, since cathepsins are associated with many different cancers and are involved in processes such as blood vessel formation and tumor growth critical to all tumors. "It suggests that anything that's aggressive and metastatic may involve these proteases and respond to an inhibitor," he said, adding that the inhibitor would likely be used in conjunction with other therapies.

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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