Cancer researchers have long sought an alternative treatment to chemotherapy that can destroy tumors without damaging the rest of the body. A new study with mouse and human tumors may put such a treatment within reach.
Designing drugs to target cancer is a challenge because cancerous cells are well camouflaged within otherwise healthy tissues. But researchers have begun to find molecular tags unique to cancer cells. Last year, Wadih Arap and Renata Pasqualini, a husband-and-wife team of cancer biologists at the M. D. Anderson Cancer Center at the University of Texas, Houston, identified a protein called GRP78 expressed by prostate cancer cells and not by healthy tissues. They knew they'd found a promising drug target because GRP78 is expressed on the cell surface, where it's easily accessible to drugs. Additionally, a drug targeted to GRP78 should be unlikely to attack healthy cells because GRP78 is a so-called stress response protein which is only expressed on the surface of cells under stressful conditions such as those that occur within the oxygen-poor lump of a tumor.
To test GRP78 as a target, a team led by Arap and Pasqualini designed a short string of amino acids that binds specifically to the surface of the GRP78 protein. They then fused this string to a small corkscrew-shaped protein that, when internalized, triggers the cell to commit suicide. The team hoped that the hybrid molecule would act as a tumor-seeking missile when injected into the bloodstream.
The missile appears to be deadly accurate. Reporting in the September issue of Cancer Cell, the team shows that its hybrid molecule located and destroyed human prostate tumors transplanted into mice, without harming any other kind of tissue. It did the same for breast tumors. The next step, say Arap and Pasqualini, is a series of preclinical studies to determine its safety for clinical trials in humans.
Over the past decade, Arap and Pasqualini have pioneered the "smart bomb" approach to cancer therapy, says Bruce Zetter, a cancer researcher at Harvard Medical School in Boston. This study "shows how close we are getting" to putting the strategy into action.