Fish and (gene) chips
By Richard Saltus
Not your average fish: zebrafish help propel neuroblastoma research
Neuroblastoma strikes the very young, not out of some malevolent biological design, but because of genetic damage to the immature nervous system. About 40 percent of neuroblastomas begin before birth, making it the most common cancer in newborns.
In addition to conducting research directly involving patients, Dana-Farber scientists are using powerful new biomedical tools to unravel the roots of neuroblastoma and search for drugs. For example, pediatric oncologists Kimberly Stegmaier, MD, and Todd Golub, MD, of Dana-Farber and the Broad Institute of the Massachusetts Institute of Technology and Harvard University have devised a method of rapidly testing thousands of chemicals and drugs against rare cancers such as neuroblastoma.
Thomas Look, MD, with (left to right) colleagues Jeong-Soo Lee, PhD, Rodney Stewart, PhD, Rani George, MD, PhD, and John Kanki, PhD
The novel strategy uses microarrays ("gene chips") to identify compounds that cause a favorable change in the genetic activity, or "signature," of cancer cells. "Neuroblastoma arises from immature neural crest cells that have both an inability to mature and an abnormal capacity to proliferate," Stegmaier says. Although researchers have not yet found the molecular targets that cause these cells to differentiate, or specialize – thereby halting the cancerous proliferation – the large-scale testing method can identify compounds that may alter a cancer cell's gene activity to resemble that of a mature cell. "Such a drug might be effective in treating the cancer," she says.
On another front, Thomas Look, MD, of Dana-Farber and Children's Hospital Boston and his colleagues are investigating the genetics of nervous system development in the zebrafish, a small, brightly-striped and nearly transparent animal that reproduces rapidly and which, literally, provides a window on the formation of internal organs and systems.
Jeong-Soo Lee, PhD, a postdoctoral fellow in Look's lab, is creating a zebrafish equivalent of neuroblastoma for genetic research and for testing potential treatments. His strategy in the project, which is supported by a gift from the Durand family, is to insert into zebrafish embryos a cancer-causing oncogene, MYCN, that drives the most aggressive and hard-to-treat form of neuroblastoma in humans. Lee is devising a way to activate the gene at the appropriate time so the fish develop neuroblastoma but don't die before they can be studied.
Rodney Stewart and co-workers are studying nerve development in zebrafish for clues to neuroblastoma.
Other investigators are hunting genes involved in embryonic growth of the nervous system. "Some of these genes have already been identified, and we're looking for mutations among neuroblastoma patient samples," says Dana-Farber postdoctoral fellow Rodney Stewart, PhD. Colleague Rani George, MD, PhD, is using a cutting-edge technique for finding small genetic alterations, called single nucleotide polymorphisms, that might reveal mutations in molecules that regulate nerve-cell growth.
Look's lab also runs tests on most of the neuroblastoma tumors taken from patients in the United States and Australia, to help determine whether these individuals are at low, intermediate, or high risk of cancer recurrence. The results can guide physicians toward the best treatments, says Lisa Moreau, supervisor of the DFCI Neuroblastoma Reference Library.
