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
Sarcomas and Sick Kids
In a report published in 1997, Edmond S. Massuda and his colleagues at the University of Wisconsin Children's Hospital in Madison described their experiments with a type of cancer called alveolar rhabdomyosarcoma—the most common type of soft-tissue carcinoma among children. This sarcoma is typically characterized by a translocation of chromosomes 2 and 13 that fuses the genes PAX3 and FKHR, both of which encode transcription factors (proteins that bind to DNA and switch other genes on and off). Normally, the PAX3 protein organizes embryonic muscle development, and FKHR is widespread. The fusion protein created from the melding of these genes causes muscle cells to remain immature and hence susceptible to other cancer-promoting events.
The investigators showed that this fusion protein is about a hundred times more effective at activating PAX3-regulated genes than PAX3 itself. Massuda and his coworkers took advantage of this property by taking the gene for diphtheria toxin A—a potent cellular poison—and modifying it so that it would be switched on only in the presence of the PAX3 protein. They then added that carefully crafted DNA to different strains of cultured cells, some of which carried the PAX3-FKHR mutant. Sure enough, the additional DNA selectively killed those cells that manufactured the fusion protein. Furthermore, when they added the fusion gene to otherwise normal cells, those cells also died in the presence of the PAX3-regulated toxin. Although the thought of injecting toxin genes into patients and trusting a bit of DNA alongside to keep them from harming the rest of the body may seem dangerous, the results from these experiments give hope that the effects will be specific to the tumor.
Like the cancer Massuda is trying to cure, Ewing sarcoma is one of the most common connective-tissue tumors in children and young adults, although it more commonly affects bone rather than soft tissues. It also stems from a chromosomal rearrangement, in this case the fusion of a gene from chromosome 22 with one from chromosome 11. The resultant protein transforms normal bone cells into cancer cells. In laboratory experiments, cultured bone cells proliferate rapidly when one adds this fusion protein and, conversely, stop dividing when it is removed—making the aberrant protein an ideal therapeutic target.
One new technology for getting rid of a particular protein in the cell is called small interference RNA (siRNA). In 2004, a team of clinical scientists headed by Howard A. Chansky at the University of Washington School of Medicine in Seattle reported on their successful application of this tool, which is both powerful and specific, to the task of suppressing the fusion protein responsible for Ewing sarcoma. The approach uses many short pieces of RNA that carry the complementary sequence to the fusion gene's RNA. The interfering RNA binds to its target to form a double-stranded molecule that the cell perceives as a virus and snips apart. Without its RNA template, new copies of the fusion protein cannot be made, and existing copies are soon degraded. Using this strategy, Chansky and his coworkers silenced the mutant gene in Ewing sarcoma cells in culture, thereby preventing further cell division. These results represent the first use of siRNA to target the RNA that cancer cells make, and this approach will almost certainly lead to new therapies.
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