New view of leukemia cells identifies best treatment options, Stanford researchers say

July 22, 2004

STANFORD, Calif. - People diagnosed with acute myelogenous leukemia usually receive the most commonly effective chemotherapy as a first line of attack, but it doesn't work for everyone. Faced with these resistant cancers, doctors move on to the next most effective treatment or perhaps a drug still in development. This process is time-consuming and can cost patients years of damaging therapy with no remission.

Speeding up this lengthy process is one goal of research by Garry Nolan, PhD, associate professor of microbiology and immunology at the Stanford University School of Medicine. He reports a new technique for getting AML patients on the right drug the first time in the July 23 issue of Cell.

Although all people with AML have a cancer of the same type of white blood cells, those cells behave very differently from person to person. By watching those behaviors, Nolan said doctors could quickly identify patients who need stronger treatment or less common chemotherapy drugs.

AML is the most common form of leukemia, with about 10,500 new cases diagnosed each year. The cancerous white blood cells divide out of control and drown out the other types of cells normally present in the blood. People with the disease tend to bruise easily because their blood doesn't contain enough platelets to clot, and they have a shortage of red blood cells, causing fatigue.

Nolan equates his technique to figuring out which people in a room are more aggressive, noting that you can't always tell at first glance. "But if I go around and kick everybody in the shin, I can see their response and learn something about that person," he said. Exposing cancer cells to different molecules is like kicking them in the shin, and Nolan's technique is the snapshot that reveals how the cell behaved. Those cells that simply look surprised are fairly normal and will probably respond well to drugs; those that glower need special treatment.

The cellular expressions Nolan watches are message-carrying pathways that translate a signal in the environment into action in the cell's nucleus. In all cells, a carefully orchestrated network of molecules passes messages between the cell's surface and the nucleus. Molecules that relay those messages follow a strict order in healthy cells, always handing the note - in this case, a phosphate atom - to the next molecule in line.

In cancerous cells, those highly regulated note-passing brigades grow independent. Molecules hand notes to the wrong counterpart, and sometimes write a note of their own and pass it along. A signal at the cell's surface saying "stop dividing" may get handed to a neighboring pathway where it becomes a signal to divide rapidly - a hallmark of cancer cells - or may get destroyed altogether.

These disturbances aren't visible just by looking at a tumor sample. Nolan got his first glimpse inside the cell's machinery using a technique developed by postdoctoral scholar Omar Perez, PhD. He harnessed a decades-old device called flow cytometry to act as a hidden security camera monitoring the note-passing molecules. The data is a snapshot of which molecules have a phosphate note in hand and which don't in response to normal signals that a cell would encounter.

Postdoctoral scholar and first author on the paper Jonathan Irish, PhD, applied Perez' technique to samples from healthy people, people with AML who responded to chemotherapy and people whose AML did not respond to the initial chemotherapy attempt. He monitored six of the molecular handoffs to see which differed when the cells were exposed to five different signals they would normally encounter in the body.

What he found was striking. Doctors usually treat a cancer as a single, uniform entity. When they take a sample to determine how far the cancer has progressed, the entire cancer gets graded on a scale of 1 to 4, with 4 being the most severe. But Nolan and Irish found that many different populations can exist within a cancer at any point in time. Some of these populations are farther along in their cancerous path than others and were passing a greater number of notes to the wrong counterpart.

A major difference between people who did and did not respond to chemotherapy was the way in which their cells responded to environmental signals. The cells that handed messages down the wrong set of pathways were able to avert the normal cell-death signals triggered by chemotherapy.

Learning to recognize the pathways most commonly disrupted in aggressive cancers could help researchers predict which patients won't respond to standard chemotherapy. Doctors could immediately propose that the person consider less common therapies.

"This is the first time we've been able to look at cancer signaling messages in a population of individual cells to distinguish treatment options," Nolan said. What's surprising is that the equipment was around for decades before Perez and then Irish honed the new technique. Nolan said flow cytometry machines are widely available to doctors treating AML and other cancers, making the technique practical and helpful to doctors.

In follow-up experiments Nolan hopes to correlate the patterns in the note-passing network to how well the patients responded to different forms of chemotherapy and how long their remission lasted. Armed with that information, doctors can help patients get the best treatment for their disease sooner.
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Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.

Stanford University Medical Center

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