Chemotherapy works through the mitochondria

From the final NCI cancer bulletin (stopped due to funding issues): it's not specific to breast cancer, but investigated how chemo works

http://www.cancer.gov/ncicancerbulletin/010813/page6

Busting a Myth about How Chemotherapy Works

Dr. Anthony Letai

Dr. Anthony Letai had just begun his first year of medical school when his mother was diagnosed with advanced colon cancer. As doctors began to treat her disease, she asked a question that her son is still trying to answer: How does chemotherapy work?

Chemotherapy kills rapidly dividing cells, her doctor had explained. At the time, Dr. Letai found this commonly held view to be "vaguely unsatisfying." As he learned more about cell biology and started a research lab at the Dana-Farber Cancer Institute, his dissatisfaction grew. The answer does not explain, for instance, why some cancers respond to chemotherapy and others do not.

"There are too many bad cases of cancer that seem to grow rapidly and resist chemotherapy, and too many that grow slowly and respond well to chemotherapy," Dr. Letai said recently. Although some textbooks and websites say that chemotherapy works by targeting rapidly dividing cells, in fact, there is limited evidence to support this idea.

"Chemotherapy has cured millions of people, but we don't know why it works," Dr. Letai said.

Profiling Cell Death

In recent years, however, an alternative explanation for how chemotherapy works has emerged from studies of mitochondria, the energy-producing organelles of cells. Mitochondria, it turns out, also play a role in a form of cell death known as apoptosis; this biologic process allows cells to "commit suicide" rather than to pass abnormalities on to the next generation of cells.

Cartoon illustrating the idea that some cancer cells are more ready to die when exposed to chemotherapy than others. Cells near the cliff are "primed" for cell death, or apoptosis. (Illustration by Kris Sarosiek)

Building on this work, Dr. Letai and his colleagues recently demonstrated that some cancer cells are "more ready" to commit suicide through the apoptotic pathway than others, at least in the lab. Differences in this state of readiness—which the researchers call "priming"—may help explain the different responses patients have to chemotherapy, the researchers concluded.

They made the discovery by profiling stored cells from patients treated for acute myelogenous leukemia (AML). "We found that the patients who did best [after chemotherapy] were the ones with the most primed leukemia cells," Dr. Letai said. "These patients are the ones who stay in remission after chemotherapy."

Many patients with AML respond to chemotherapy and never relapse, whereas other patients do not respond at all or respond but eventually relapse. The new findings, reported in Cell, suggest that differences in priming may determine a patient's initial response to chemotherapy as well as the risk of relapse.

Expanding Knowledge

The Cell paper expands our knowledge about "the important role that mitochondria play in cell death," commented Dr. Douglas Green of St. Jude Children's Research Hospital, who studies apoptosis but was not involved in the research.

"Cancer cells show differential priming for death, and these differences correlate with the clinical response to conventional therapy," Dr. Green wrote in an e-mail. Further research could lead to new drugs that affect this pathway, although more work is needed to understand the components of the pathway, he added.

In the Cell study, Dr. Letai used an existing drug to increase the priming of cancer cells, which, in turn, made the cells more likely to die after exposure to chemotherapy. This finding suggests that it may be possible one day to identify patients whose cancer cells are not sensitive to chemotherapy and make the cells responsive.

"This study was a proof of concept," said Dr. Thanh-Trang Vo, the first author of the report. "A prospective study is necessary to see how well this profiling will help us to predict patient outcomes."

A New Test

Although AML was the focus of this work, the researchers previously had linked mitochondrial priming and sensitivity to chemotherapy in other cancers, including ovarian, multiple myeloma, and acute lymphocytic leukemia.

The innovation that made the current work possible was a test known as BH3 profiling. The test provides a measure of how close a cell is to the threshold of death based on the activity of proteins associated with the cell-death pathway. Cancer cells that are more primed than the patient's hematopoietic stem cells are most likely to respond well to chemotherapy, the researchers found.

Dr. Stephen Nimer, director of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, called the study "illuminating." "More research is needed to help us understand why the average patient's cancer can resist the basic chemotherapy approaches," he continued, "and this work is a step in that direction."

Follow-up studies to confirm the Cell results are under way, noted Dr. Nimer, who is also a scientific advisor to Gabrielle's Angel Foundation for Cancer Research. The foundation recently provided funding for this work to Dr. Letai and his collaborator, Dr. Scott Armstrong of the Memorial Sloan-Kettering Cancer Center.

Levels of Complexity

For multicellular organisms, the cell-death pathway in mitochondria is a kind of failsafe measure, explained Dr. Vo, who is now a postdoctoral fellow at the University of California, Irvine. "If a cell is no longer fit for survival, it can activate the suicide pathway in mitochondria to prevent its own cellular dysfunction from harming the whole organism."

The biologic complexity of apoptosis is illustrated by the fact that no single protein could provide the readout the researchers needed, noted Dr. Tito Fojo of NCI's Center for Cancer Research, who studies drug resistance but had no role in the study.

"As researchers and clinicians, we would always like to measure just a single thing, such as a protein, and then select a drug for patients based on the test," he continued. "But this is not realistic because cells just aren't that simple."

How chemotherapy kills cancer cells is also complex, noted Dr. Fojo. The idea that these drugs kill rapidly dividing cells remains popular even though it has never been demonstrated, he added. "I hear people say this all the time, and I always ask them, 'Where are the data for this?'"

Current research shows that different sets of genes are associated with the proliferation of cancer cells and their sensitivity to chemotherapy.

"We know unequivocally that drug sensitivity has nothing to do with proliferation—these are two distinct properties of the cell," Dr. Fojo said. Support for this idea comes from the Cell study, which found no correlation between the rate of cell proliferation and sensitivity to chemotherapy among the samples studied.

Potential Clinical Applications

With his colleagues in the clinic, Dr. Letai is planning a study to see if BH3 profiling can prospectively identify patients with AML who need—or who do not need—a bone marrow transplant after their first remission. He believes the test might also help identify older patients who may not benefit from induction chemotherapy, which can be difficult for older patients.

Progress in the field will come as researchers understand and learn to manipulate the pro-apoptotic proteins of the BCL2 family, Dr. Green predicted. "We do not fundamentally understand how some of these proteins actually function, but we're getting there."

"Ultimately," he continued, "we will have drugs that directly activate these proteins, or that directly inhibit them, and these will be invaluable." In the meantime, Dr. Letai's lab will carry on its research, as summarized in a tagline on its website: "Working to restore the death sentence to cancer cells since 2004."

As for Dr. Letai, he pointed out that researchers can learn a lot from questions like the one his mother asked years ago. "The questions lay people ask can often harshly expose the limitations of our knowledge," he said.