Research makes it possible to predict how cancers will respond to chemo

Challenging a half-century-old theory about why chemotherapy agents target cancer, scientists at Dana-Farber Cancer Institute have devised a test that can predict how effective the drugs will be by determining whether a patient's tumor cells are already "primed" for death.

In a study published online by the journal Science on Oct. 27, the researchers report that cancer cells that are on the verge of self-destruction are more likely to succumb to certain chemotherapy agents than cancer cells that have yet to reach that stage. The discovery suggests that it may be possible to predict which cancer patients are most likely to benefit from chemotherapy, as well as to make chemotherapy drugs more effective by pushing tumor cells closer to the point of suicide.

"Many chemotherapy agents work by damaging structures within cancer cells, particularly DNA and microtubules [tiny tubes used for a variety of cell functions]," says the study's senior author, Anthony Letai, MD, PhD, of Dana-Farber. "When the damage becomes so extensive it can't be repaired, the cells initiate a process known as apoptosis, in which they sacrifice themselves to avoid passing the damage on to their descendants."

The researchers found that cancer cells that are closer to this apoptotic threshold are more susceptible to chemotherapy than other cancer cells - and that it's possible to measure how close cells are to that breaking point.

Letai and his colleagues developed a technique called BH3 profiling to make that measurement. The technique focuses on mitochondria - cell structures where the decision is made whether or not to die - and proteins known as the BCL-2 family. Within the mitochondria, BCL-2 proteins act like bickering in-laws, some promoting apoptosis, others resisting it. The faction that predominates determines whether the cell lives or embarks on apoptosis.

The measuring technique uses bits of protein known as BH3 peptides from members of the BCL-2 family that spur apoptosis. Scientists prepare cells to allow entry of these BH3 molecules and examine whether holes begin forming in the mitochondria, a key step in apoptosis. A fluorescent dye enables scientists to measure whether the holes are forming. By adding BH3 peptides to the samples and measuring how much was needed to kill the cells, the investigators could gauge how close the cells were to apoptosis. Cells that needed the least BH3 peptide to be nudged into the suicide program were considered primed for death.

Research in the Letai lab centers on understanding how cells decide to make the commitment to apoptosis. We focus on the role of BCL-2 family proteins, as these proteins play the key roles in deciding whether cells should commit to apoptosis, and in executing the mitochondrial permeabilization that is the required hallmark of mitochondrial apoptosis.

An important past and continuing interest is understanding how BH3-only proteins signal death. We proposed the concept that BH3-only proteins can play two different roles: activators, which can directly activate BAX and BAK; and sensitizers, which antagonize antiapoptotic proteins like BCL-2 and MCL-1. We are studying how some cells can be "primed for death" by possessing large amounts of activator BH3-only proteins sequestered by anti-apoptotic proteins. We can detect such cells by means of a technique we developed called BH3 profiling.