Divide and conquer
Sorting lymphomas by gene signatures aids drug targeting
By Richard Saltus
Scientists are dividing lymphomas into different genetic types based on the mutations that cause them. Above, Jennifer Brown uses a family tree to study rare cases of inherited lymphoma.
In the winter of 2002, rapidly worsening leg pains and near-paralysis sent Carolyn Punzelt to an emergency room, where physicians discovered tumors encroaching on her spinal cord. Radiation treatment shrunk the cancer, forestalling immediate danger. After several biopsies, the Castine, Maine, woman was diagnosed with an aggressive form of non-Hodgkin's lymphoma (NHL), a cancer of disease-fighting white blood cells.
Despite their scary description, about 50 percent of fast-growing, aggressive non-Hodgkin's cases can be cured with chemotherapy. Punzelt's cancer, unfortunately, fell into the other half. Months of standard chemotherapy regimens failed to stop her disease and dangerously weakened her immune system.
At Dana-Farber's pharmacy, Carolyn Punzelt picks up a supply of the experimental drug that has kept her lymphoma in remission for more than three years.
"At that point my oncologist said, 'OK, you're going to Dana-Farber,'" recalls Punzelt. "He said, 'If you don't do anything, I give you less than a year to live.'"
That was in 2003. Today Punzelt is 75 and well, with no detectable cancer. A drug that was in clinical trials at Dana-Farber, enzastaurin, did what the toxic, cell-killing chemotherapy could not — put her in long-term remission. Taken as a pill, enzastaurin pinpointed a precise genetic defect within her cancer cells and shut down their growth. There were few side effects. Her hair, decimated by the chemotherapy, grew back.
"It's really miraculous," she says. "I'm active in a number of groups; I'm in the vestry of my church, and I live in a huge old house that needs a lot of work." Oncologists in Maine monitor her remission, and she makes occasional 500-mile round trips to Dana-Farber/Brigham and Women's Cancer Center to see her doctor, David C. Fisher, MD, and to pick up enzastaurin supplies.
Punzelt's story is more than a single patient's reprieve; it represents a still-evolving, divide-and-conquer strategy using technology that takes "snapshots" of how all the genes in a cell are behaving. The approach is this: Separate tumors into subgroups by their distinctive genetic activity patterns. Using standard therapies, treat the cancers whose profiles suggest favorable outcomes. For those with poor-outcome gene profiles, develop and test new drugs to attack abnormal links in the cancer cell's chain of molecular signals, or "pathways."
"We have a major commitment to understanding the genetic pathways that enable lymphoma cells to survive, and manipulating them with rational, targeted therapy," says Margaret Shipp, MD, a Dana-Farber oncologist and director of the Dana- Farber/Harvard Cancer Center Lymphoma Program.
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