Cellular signaling sheds light on new cancer therapies

By revealing the inner workings of a common cell-to-cell signaling system, U-M biologists have uncovered new clues about mysterious and contentious creatures called cancer stem cells.

The findings also have implications for a high-profile breast-cancer drug trial getting underway at the Medical School and two other institutions.
Dr. Max Wicha says new stem cell developments may have implications for a breast-cancer drug trial at the Medical School. (Photos courtesy Medical School)

In the groundbreaking trial, researchers are combining chemotherapy with a drug that blocks the Notch signaling pathway, which helps regulate fetal development and is active in most organ systems throughout a person's life.

The aim is to use so-called Notch inhibitors to attack cancer stem cells, the small fraction of stem cells inside a tumor that help it survive and that fuel its growth.

But a big concern is that the Notch inhibitors, while helping to destroy cancer stem cells, also might kill or harm the normal, healthy stem cells critical to a patient's survival such as blood-forming stem cells in the bone marrow.

New results from Dr. Ivan Maillard and his colleagues may allay some of those fears. The researchers showed that blood-forming stem cells in mice survive just fine when the Notch signaling pathway is experimentally blocked.

"Our data indicate that normal blood-forming stem cells should not be damaged by the Notch inhibitor drug being used in these patients," says Maillard, a hematologist and a Life Sciences Institute (LSI) researcher.

"That's important, since these patients typically need good blood stem cells to maintain their blood counts and recover from the effects of chemotherapy," he says.

The Notch findings appear in the current issue of the journal Cell Stem Cell. Maillard's team includes researchers from the University of Pennsylvania School of Medicine, the Swiss Institute for Experimental Cancer Research and Harvard Medical School.

Dr. Max Wicha, director of the Comprehensive Cancer Center, says Maillard's results are welcome news for cancer stem cell researchers, and for the 30-patient metastatic breast-cancer drug trial that launched last month at his center, at the Baylor College of Medicine in Houston and at the Dana-Farber Cancer Institute in Boston.
"These patients typically need good blood stem cells to maintain their blood counts and recover from the
effects of chemotherapy."

— Dr. Ivan Maillard

"A lot of what we're thinking about now, therapeutically, is trying to find ways to attack these cancer stem cells because we think that's really what drives the malignancies," says Wicha, who was not involved in the Notch study. "Ivan's paper, combined with our own work, shows that there may be differences between normal stem cells and cancer stem cells, and perhaps those differences can be exploited therapeutically."

The cancer stem cell theory is controversial. Some researchers are not convinced cancer stem cells exist.

The current two-stage drug trial uses a Notch inhibitor originally developed by Merck for Alzheimer's patients in the late 1990s, followed by chemotherapy. The intent is to use the Notch inhibitor to make cancer stem cells sensitive to the chemotherapy — a one-two punch to knock out tumors.

If the treatment is effective, the results could help sway some skeptics of cancer stem cells.

The Notch pathway sends signals from a cell's surface membrane into its nucleus. Those signals activate genes that instruct the cell to make proteins that perform various tasks.

In the lab, Maillard and his colleagues were able to prevent Notch signals from activating mouse target genes using two independent techniques.

Many scientists have long assumed that blood-forming stem cells need Notch signals to function properly. But Maillard's team found that the signals are not required for the maintenance of blood-forming stem cells in adult mice.

In addition to his position as a research assistant professor at LSI's Center for Stem Cell Biology, Maillard is an assistant professor of internal medicine and an assistant professor of cell and developmental biology at the Medical School.

Funding for the Notch study was provided by grants from the National Institutes of Health, The Leukemia & Lymphoma Society, the Swiss National Science Foundation and the Damon Runyon Cancer Research Foundation.