"Rewiring" Cells to Treat an Aggressive Breast Cancer ▲ NCI Cancer Bulletin for May 15, 2012 - National Cancer Institute

NCI Cancer Bulletin for May 15, 2012 - National Cancer Institute

"Rewiring" Cells to Treat an Aggressive Breast Cancer

A new treatment approach aims to make breast cancer cells more susceptible to chemotherapy.Yellow cells responded (many will die), red cells are alive but not dividing, and green cells are growing and dividing.  (Photo courtesy of Neil Ganem, David Pellman, and Michael Yaffe)

Cancer cells develop genetic changes over time, and this is one reason that a drug may stop working in a patient. Such changes often alter signaling pathways that control cell growth. A new study suggests that learning more about how these pathways function in cancer cells and using this knowledge to "rewire" signaling networks could lead to novel treatments.

In the study, published May 11 in Cell, researchers treated breast cancer cells in the lab with targeted therapy and chemotherapy. Rather than giving the treatments simultaneously, however, the investigators pretreated the cells with a targeted drug, which made the cells more susceptible to chemotherapy.

"This study suggests that you can therapeutically rewire cancer cells to increase their sensitivity to chemotherapy," said lead investigator Dr. Michael Yaffe of the Massachusetts Institute of Technology (MIT). "Cells are complex systems," he continued. "We're blocking one pathway, and then allowing the rewiring to occur."

Sensitizing Cancer Cells


In the sequential approach, the researchers first exposed the cells to erlotinib (Tarceva), which blocks the activity of a protein called epidermal growth factor receptor (EGFR). Then, after at least 24 hours, the cells were exposed to doxorubicin, a commonly used chemotherapy drug.

Dr. Yaffe and his colleagues used cells from women with triple-negative breast cancer, an aggressive form of the disease that disproportionately affects younger women and African Americans. New treatments are needed, and based on the study results, the researchers have begun to plan a clinical trial.

"These are exciting findings," said Dr. Dan Gallahan of NCI's Division of Cancer Biology. "They suggest that we can use knowledge of signaling pathways to make cancer cells more sensitive to drugs we already have, such as first-line chemotherapy agents."

After being exposed to erlotinib, about 40 percent of the cell lines tested in the study responded to doxorubicin. Seventy-two hours after the time-delayed administration of the two drugs, none of the cells that had responded were still alive, the researchers found.

Erlotinib made the cancer cells "exquisitely sensitive to a DNA-damaging agent," noted Dr. Gallahan, who is also director of NCI's Integrative Cancer Biology Program (ICBP), which helped fund the study.

"We know that cancer cells evolve and develop resistance to therapies," Dr. Gallahan continued. "This study illustrates how new information about the signaling pathways in cancer cells that emerge from a systems-biology approach can be used to manipulate the cancer."

Clues from Systems Biology


Dr. Yaffe's lab studies how cells respond to DNA damage and how cells integrate information. Recently, the lab developed new ways to simultaneously study multiple signaling pathways and networks within cells—an approach that is sometimes called systems biology.

These findings suggest that we can use knowledge of signaling pathways to make cancer cells more sensitive to drugs we already have.
—Dr. Dan Gallahan

In the first phase of the study, the researchers tested the effects that combinations of drugs given at different time intervals had on cancer cells. Hoping to move rapidly to a clinical trial if they found a positive result, the researchers focused on drugs that are already approved or being tested in patients.

"Based on experiments in the lab, we reasoned that it might be possible to take cells that were not particularly sensitive to a drug and convert them to a state in which they are sensitive," explained Dr. Yaffe. The general idea of changing the state of a cell is not new, he noted, but the approach evaluated in the current study had not been tried in triple-negative breast cancer.

Previous clinical trials combining erlotinib and chemotherapy without the specific time-staggered dosing had produced only modest results, Dr. Yaffe noted. His team also tested their approach in mice and observed positive results.

The researchers also found that another signaling pathway associated with cell death was activated in the cells that responded to the time-staggered approach. "The systems biology analysis was able to show why the time-staggered administration was so effective at killing the cancer cells," said Dr. Yaffe.

Erlotinib seemed to "unmask" a signaling pathway associated with programmed cell death, or apoptosis, that was not available in untreated cells. This pathway involves a protein known as caspase-8, which could be a marker of response to the treatment, the authors said.

The cells that showed the most dramatic response to the time-staggered administration had high levels of signaling through EGFR, regardless of whether EGFR itself was mutated, or expressed at high or low levels.
Additional experiments suggested that other combinations of targeted drugs and DNA-damaging agents used in the same fashion may work for some lung cancers.

Future Challenges

The systems biology analysis was able to show why the time-staggered administration was so effective at killing the cancer cells.
—Dr. Michael Yaffe

As he looks to the future, Dr. Yaffe sees two primary challenges. One is finding ways to measure EGFR activity in human tumors as a marker to identify candidates for the treatment. The other challenge is the heterogeneity of tumors. If a tumor has a population of cells actively signaling through EGFR and another population that is not, this approach might not kill the population that is not signaling through EGFR.

"Tumor heterogeneity is always an issue [when treating cancer], and our approach does not get around that," said Dr. Yaffe. Nonetheless, he continued, this approach has the potential to improve treatment for some women with triple-negative breast cancer using drugs that are already available.

As a next step, the researchers are collaborating with engineers at MIT to try to develop a therapy that combines the two drugs and has the delay built in. One possibility is a coated nanoparticle with an EGFR inhibitor on the outside and doxorubicin on the inside, which the researchers are preparing to test in mice.

"We don't have a great understanding of the crosstalk between signaling pathways, and that is a major limitation in using targeted anticancer drugs," said Dr. Yaffe. But he is optimistic that it will be possible to improve cancer treatments "with drugs we already have by using systems biology to understand how best to combine these agents."
—Edward R. Winstead