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
Going After the Genes
Like other cancers, sarcomas are products of genetic mutations, which can take many forms. One particular category of genetic errors, called chromosomal translocations, is responsible for several sarcomas.
A chromosome is a single long strand of DNA—thousands of times longer than a cell is wide. When a human cell is preparing to divide, it copies each of its 23 pairs of chromosomes so that each daughter cell can receive a complete set. Occasionally, a strand of DNA will break during this process. The cell usually mends these fractures correctly, or, if it cannot, trips the self-destruct switch (leading to programmed cell death, or apoptosis). But sometimes a cell will incorrectly join two or more different chromosomes, yielding a translocation. If the cell subsequently escapes its own destruction, daughter cells can inherit too many or too few copies of that piece of chromosome. Furthermore, if the DNA is snapped and incorrectly repaired in a region that specifies a protein, that valuable piece of the genetic code—that gene—may be destroyed, leaving the cell with only one remaining copy on the unbroken partner in the chromosome pair. Another possibility is that the improperly repaired DNA will encode a "fusion protein," made from the sequences of two different genes spliced together. Many such fusion proteins are merely ineffective, like a bicycle with oars instead of pedals, but some can be dangerous. If the original performed some critical function in the cell, such as regulating cell division, the fusion protein can cause big problems.
These breaking-and-joining events do not happen randomly, and certain translocations cause specific kinds of cancer. One example is the abnormal inheritance of an extra copy of the long arm of chromosome 12, which causes a version of the most common soft-tissue cancer, liposarcoma—the class of sarcoma that develops from fat cells. Thanks to recent advances in "gene profiling" (a technique that measures gene activity), scientists have identified a cause of one subset of this class, the so-called dedifferentiated liposarcomas.
With two normal copies of chromosome 12 plus the extra fragment, cells manufacture too much of the protein encoded by one of the resident genes: the cyclin-dependent kinase 4 gene, a mouthful that usually goes by the shorthand CDK4. As its name indicates, the CDK4 protein is a kinase—an enzyme that adds phosphate groups onto other proteins as a means of controlling how active or inactive they are. It so happens that this particular kinase acts on one of the master switches of cell division, the stoutly named retinoblastoma tumor suppressor, or RB, which acts through a DNA-binding protein called E2F. A glut of CDK4 causes RB to have an excessive number of phosphate groups attached, thereby jamming the cell-division switch in the on position—a hallmark of cancer.
Once scientists understood this chain of events, they hypothesized that blocking CDK4 might slow the spread of liposarcoma. One candidate drug is flavopiridol, which inhibits several kinases, including CDK4. Our colleagues Gary K. Schwartz and Samuel Singer at Memorial Sloan-Kettering have shown that this drug destroys liposarcomas in the culture dish and in mice that carry human liposarcomas. Several clinical trials are now testing flavopiridol for various cancers.
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