FEATURE ARTICLE
Fighting Cancer Through the Study of Sarcomas
Although rare, cancers of the muscle, bone or fat carry the same molecular errors as other tumors, making them ideal subjects for the discovery of new therapies
Igor Matushansky, Robert Maki
GIST Deserts
Although siRNA and similar experimental avenues for fighting cancer are still far from routine clinical application, the use of imatinib for treating GIST (sparked by the recovery of the Finnish woman) has now become accepted for certain advanced cases. How exactly does the drug work? GIST is usually caused by mutations in a gene called—no kidding—v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog. This tongue-twister, called KIT for short, codes for a protein also named KIT, a kinase like CDK4, but one that adds phosphate groups only to tyrosine—one of the 20 different types of amino acids that make up human proteins.
Tyrosine kinases are often embedded in the outer membrane of the cell. There, they can receive signals from the immediate environment and transmit them to the nucleus (via a chain of other messengers), thereby helping to determine which genes are turned on or off. Overactive tyrosine kinases cause many kinds of tumors.
Although the KIT protein shows up in other cancers, such as small-cell lung cancer and seminoma of the testes, only GIST contains mutations in the gene that cause unregulated activity. In a 2001 paper, David A. Tuveson, then a postdoctoral fellow in the laboratory of Tyler Jacks at MIT, showed that imatinib interferes with normal and mutant KIT and inhibits the growth of cultured GIST cells that contain the latter. These observations helped to hasten the Food and Drug Administration's approval of imatinib for the treatment of GIST tumors that have spread so widely that surgery is impossible—granted a scant 10 months after the publication of the original case study. (Customarily, experimental drugs are first approved for use in people who have exhausted their other options.)
To grasp the striking success of imatinib, one needs to understand that prior to its use there were no good treatments for GISTs. Most of these tumors are highly resistant to chemo- and radio-therapy, and multiple surgeries were the only palliative option. Now, the combination of surgery and imatinib benefits more than 80 percent of patients. Unfortunately, this upswing is only a respite in some cases. The tumors vary in their genetic make-up, which presumably explains the slow remedy seen by some patients and the unresponsiveness of others. The latter group often carries tumors that have little or no KIT protein, a variety that can also be found among patients who initially respond well to the drug, but worsen as the susceptible cells die off, leaving others to spawn new tumors that resist imatinib.
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