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A new road to cancer
Korsmeyer's finding put apoptosis — or failed apoptosis, actually — squarely on the map as a fundamental process in initiating and maintaining cancer. The Bcl-2 gene became the first in a new class of oncogenes (genes that cause cancer) that function by keeping cancer alive.
Korsmeyer, who became director of Dana-Farber's Molecular Oncology program in 1998, and others made a string of discoveries about a family of molecules that regulate apoptosis — a word derived from Greek, meaning "falling leaves."
Bcl-2 was the founding member of a molecular family that includes several branches, some of them rivals. On one side are the survival—promoting Bcl-2 and its kin; opposing them are pro-apoptotic members such as BID, BAX, and BAK. At any given time, a cell's fate hangs in the balance of a life-or-death battle between pro-survival and pro-apoptotic signals.
Korsmeyer and his Dana-Farber colleagues have launched the first efforts to treat cancer by tipping the balance in favor of cell death. To be specific, they hope to disable the survival molecules that have been holding their pro-death counterparts at bay. The idea is that the pent-up death signals will rush in and force the cancer cells to commit suicide.
"There's reason to believe that cancer cells are dying to die."
—Anthony Letai, MD, PhD
"Cells are rigged to die," Korsmeyer explained. "They have to have some intentional signaling, often in the form of growth factors, to keep them going. But when you take away the goodies — the survival factors — then the death program gets turned on."
In cancer, the death mechanism may be very active, but if survival signals hold the edge, they protect the cell from death. Yet this high-stakes dynamic is something researchers believe they can exploit.
"There's reason to believe that cancer cells are dying to die," says Anthony Letai, MD, PhD, an Institute researcher formerly in Korsmeyer's lab and now heading his own. "They are on the threshold, generating death signals because cancer cells violate lots of normal rules, and these violations are punishable by death. One way cancer cells escape is through the presence of excess Bcl-2 or similar molecules that thwart apoptotic suicide."
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