Pathways to Cancer: Growth of normal cells is regulated by signals along two major pathways — one that stimulates cell division and one that blocks it. Malfunctions along either pathway can lead to chaotic, malignant growth. Gene profiling can identify faulty genes in signaling pathways, improving diagnosis and singling out targets for new drugs.
Staff illustration by John DiGianni adapted from Scientific American.
Spin-off of the human genome project
Two developments have fueled the gene-profiling momentum of the past year or two. First, the decade-long human genome project has virtually finished deciphering the genetic code of all the human cells — including many abnormalities implicated in cancer. Second, the invention of gene "micro-arrays" or "gene chips" makes it possible to quickly identify thousands of genes in a cell and determine their degree of activity.
The recent series of publications by Dana-Farber scientists all involve the work of Todd Golub, MD, a pioneer in cancer gene expression profiling at DFCI and the Whitehead Institute. Golub was the first scientist, in 1999, to show that the method could distinguish two types of cancer that closely resemble each other (see Winter/Spring 2000 Paths of Progress). The flurry of subsequent papers "is gratifying," he says, "because all of the work coming out now is pushing the envelope a little bit further compared to our first paper."
One of the most talked-about new reports, whose lead author is Scott Armstrong, MD, PhD, of Pediatric Oncology, describes how gene chip studies of cancer cells enabled investigators to identify a unique form of leukemia. The scientists have even given it a name, "mixed lineage leukemia," or MLL. Previously, this was thought to be just a baffling, particularly hard-to-treat subtype of acute lymphoblastic leukemia, or ALL.
The study highlighted a particular gene stuck in the "on" position that seems to be key to the disease. Fortunately, pharmaceutical research-ers had previously come up with a drug that inhibits the culprit gene (known as flt-3), and the Dana-Farber contingent says this drug kills MLL cells in the laboratory. Eventually, they hope to test it against MLL in infants, who often die of the rare cancer.
By testing samples of lung cancers with gene chips, Dana-Farber scientists were able to classify them on the basis of their genetic signatures. Matthew Meyerson, MD, PhD (left), and colleague Arindam Bhattacharjee, PhD, published a report on the study last fall.
In January, a team led by Margaret Shipp, MD, of Adult Oncology, reported in Nature Genetics that it used gene profiling to distinguish between identical-looking samples of a lymphoma that is unpredictable: it can be cured in about 40 percent of cases, while it is lethal in 60 percent. It's a common form of lymphoma called diffuse large B-cell lymphoma, or DLBCL. "We took tumors from 58 patients that looked exactly the same under the microscope," she says, "and predicted on the basis of molecular profiles which could be cured with standard therapy and which could not." The prediction was strikingly accurate.
Again, as in the MLL discovery, scrutiny of gene patterns in DLBCL identified a misbehaving gene and an errant protein in the more dangerous type of the disease. Shipp views the wayward protein as a potentially valuable new target for better drugs than are now available. She learned that one such drug had already been developed for another disease, and the researchers hope to begin a clinical trial this year.
Another paper, from the lab of Matthew Meyerson, MD, PhD, of Adult Oncology, used gene profiles to distinguish several different types of lung cancer. In most cases, the technique sorted the cancers into the same categories used in traditional diagnosis. But, in one case, the genetic snapshots broke new ground: they identified a type of lung cancer that had a worse prognosis for survival than a similar-appearing cancer. This information could be useful in designing treatment plans.
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