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Molecular characteristics seen when a tumor is first diagnosed dictate what happens years later, according to Staudt's work. A tumor's molecular profile predicts how it will respond to therapy, how aggressive it will be, and whether it will spread to other parts of the body. "Molecular wiring and the difference among patients is already there," says Staudt. "It's our job to use these signatures to make predictions and ultimately change therapy."
Staudt first developed this method of measuring DNA differences in diffuse large B-cell lymphoma, the most common type of non-Hodgkin's lymphoma, using a special DNA microarray. The "lymphochip" enabled him to analyze thousands of genes in lymphoma biopsy samples. It was the first example of taking samples from people with a clinical diagnosis of a cancer and splitting those samples into two groups that were different in the expression of genes and, more importantly, in the patients' ability to be cured by current therapies. Their first paper on the lymphochip was published in 2000.
Since then, Staudt's team of 14 researchers on the NIH campus has been using the latest genome technology to profile other lymphomas and leukemias while others study breast, lung, and other cancers. In 2003, his group reported exciting results in mantle cell lymphoma and chronic lymphocytic leukemia. They used molecular profiling to identify which mantle cell lymphoma patients will have a long survival following diagnosis and which will have aggressive disease. Patients in the most favorable group have a median survival of 6.7 years, whereas patients in the least favorable group survive less than 1 year after diagnosis. Knowing whose disease is slow-moving and whose is progressing rapidly should help determine who would do well with a watchful waiting approach and who may benefit from early and aggressive treatment, possibly with new therapeutic regimens, according to Staudt.
For chronic lymphocytic leukemia, scientists had shown several years ago that there were two types of this leukemia, but the means for telling the two apart and affecting treatment choices was complex and not available to most patients. Staudt's group showed that expression of a single gene, ZAP-70, is a surrogate for this distinction. "It lends itself to a rather easy clinical test that should be available to most patients within a year," says Staudt.
Improving diagnostic accuracy is only half of it. Staudt's group also probes the pathways within the cancer cell to see which ones are important for its growth and survival. They
have clinical partners at NCI who can quickly move their findings into clinical studies and they look for partners within the pharmaceutical industry to develop drugs that will target
the pathways they uncover, offering interventions targeted to each individual's cancer.
To speed molecular profiling research, NCI has formed the Lymphoma/Leukemia Molecular Profiling Project, an international consortium of eight institutions: University of Nebraska Medical Center, British Columbia Cancer Agency, Southwest Oncology Group, University of Wuerzburg in Germany, University of Barcelona in Spain, Norwegian Radium Hospital in Oslo, and St. Bartholomew's Hospital in London. Each institute sends its patients' tumor samples to Staudt's lab for his specialized molecular profiling.
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