Method identifies cancer cells that are "primed" to die

Anthony Letai, MD, PhD

A test developed by Dana-Farber Cancer Institute scientists is the first to identify which malignant blood cells are highly vulnerable to a promising type of experimental drugs that unleash pent-up "cell suicide" factors to destroy the cancer.

The researchers demonstrated that chronic lymphocytic leukemia, CLL, which is diagnosed in 10,000 Americans each year, is an easy mark for the new drug because the cancerous cells are strongly dependent on a particular survival molecule, Bcl-2, that keeps the self-destruct signals at bay. They showed that the investigational drug neutralizes the Bcl-2 action, unleashing molecules that trigger suicide in the cancer cells, a process known as programmed cell death or apoptosis.

The research in the laboratory of Anthony Letai, MD, PhD, of Dana-Farber, is described in the January issue of The Journal of Clinical Investigation. The lead author is Victoria Del Gaizo Moore, PhD, a member of the Letai group.

Letai was a colleague of the late Stanley J. Korsmeyer, MD, of Dana-Farber, who discovered the key role in cancer played by anti-apoptosis molecules such as Bcl-2, which promote the survival of cells that are damaged or abnormal despite the body's efforts to eliminate them through apoptosis.

Inspired by this pioneering research, drug companies have begun testing novel Bcl-2 inhibiting drugs designed to restart the natural death processes thwarted by the survival molecule.

Letai said that his group has tested Abbott's investigational compound ABT-737 against cultured CLL cells with striking results. "We've treated CLL samples from several dozen patients, and each has responded to a very low concentration of the drug," said Letai. "We find it particularly interesting that the cells died within four hours."

Cells from CLL, a currently incurable disease, are vulnerable to this dramatic reversal of fortune because they are "primed for death;" they are surviving only because Bcl-2 proteins are blocking powerful cell-death molecular signals by holding them hostage. Primed cells, Letai explained, are like a car with a revved-up engine on the edge of a cliff, restrained only by its emergency brake; if the brake was released, the car would plunge over the cliff.

Drugs such as ABT-737, in effect, release the brake. The drug molecules liberate the pro-death signaling molecules from their Bcl-2 captors. These pro-apoptosis molecules – a key one is called BIM – then trigger a chain of events that cause the cell's power plants, or mitochondria, to rupture and spill out chemicals that cause the cell to die and be tagged for disposal. This class of drugs is expected to be relatively non-toxic to most normal cells, which are much less dependent on Bcl-2 function than are cancer cells to stay alive.

"It's essential to figure out which cancers are going to respond to the drug by identifying the cells that are dependent on Bcl-2 for survival," said Letai, who is also an assistant professor of medicine at Harvard Medical School. "Up to now there hasn't been a way to do this."

In developing the test, the Letai team first isolated mitochondria from cancer cells; then they exposed them to protein fragments – peptides – that were known to interact with survival molecules like Bcl-2. "If they interact, then the cell is primed to die, and the test will identify which of the survival molecules is keeping the cells alive," he added. "Then you know that to kill the cell, you have to target Bcl-2."

The researchers have dubbed the test "BH3 profiling" because the array of protein fragments are known as "BH3 domains." Letai said work is under way to make the laboratory profiling operation more automated, looking toward a time when it could be used on a routine basis to assess the vulnerability of patients' cancers to compounds that antagonize BCL-2 or related anti-death proteins.

"This is a totally new class of drugs and has the potential to be a major addition to how we treat cancer," he said.

The paper's co-authors are Jennifer R. Brown, MD, PhD, Michael Certo, Tara M. Love, PhD, and Carl D. Novina, MD, PhD, all of Dana-Farber.

The research was funded by the National Institutes of Health, the Dunkin Donuts Rising Stars Program, the Richard and Susan Smith Family Foundation, and the Sidney Kimmel Foundation for Cancer Research.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.