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Believing in Hope:

U-M researchers work to shed light on the grim world of pancreatic cancer

Written by Sally Pobojewski

Pancreatic cancer is a cruel disease. In spite of doctors' best efforts to cut out the tumor, poison it with chemotherapy and sear it with radiation, it usually comes back and spreads malignant cells to other organs in the body. Unless the tumor is detected early and removed before it spreads outside the pancreas, patients often die within a few weeks to a few months after diagnosis.

This devastating disease makes up only 2% of all cancer cases, but is the fourth most common cause of deaths from cancer in the U.S. The 43,000 Americans diagnosed last year have few reasons to hope for a different outcome.

But hope often is found in unexpected places like the animal research facility in a basement on the U-M medical campus. It is home to 1,000 genetically engineered mice that were created in the research laboratory of Marina Pasca di Magliano, Ph.D., assistant professor of surgery and of cell and developmental biology in the Medical School.

Some of these mice are dying from pancreatic cancer, but others are running around their cages, eating mouse chow and living the good life. They are the world's first genetically engineered mice to be cured of pancreatic cancer, thanks to the discovery by Pasca di Magliano and her research team, of how to turn off the activity of an oncogene, or cancer-promoting gene, called KRAS (pronounced K-ras).

In a recent series of experiments, U-M scientists turned on the mutant KRAS gene and induced inflammation in the mouse pancreas. Cells began to change and divide abnormally, until after just a few weeks, the entire mouse pancreas was filled with pre-malignant lesions. But when KRAS was turned off, the lesions regressed and pancreatic cells returned to normal within just a few days. Six months later, the mice were still cancer-free. Even in mice who developed advanced cancers, turning off KRAS resulted in the primary tumor and metastatic lesions melting away.

Other researchers have attempted to cure pancreatic cancer in a similar research mouse in which the mutant form of KRAS is always active or turned on. But in spite of many attempts by many scientists, "nobody was able to cure those mice," says Pasca di Magliano. "We figured out a genetic trick to turn KRAS on and off in the mouse. This has never been done before and it made all the difference." In a nearby building, there's another colony of research mice belonging to Diane Simeone, M.D. (Residency 1995), the Lazar J. Greenfield Professor of Surgery and director of the Pancreatic Cancer Research Program. These mice serve as living incubators for pancreatic tumors removed from U-M patients during surgery. Small pieces of a patient's tumor are implanted and grow in the pancreas of these mice. Simeone's research team and her colleague Chandan Kumar, assistant professor of pathology, can then analyze the mutant genes expressed in each patients tumor and test in mice experimental drugs designed to block the activity of those mutant genes.

"There is a significant amount of genetic diversity in these tumors," says Simeone. "It gets to the concept of personalized therapy we hope to use the mouse models we've developed to help us understand which treatments to give to specific patients in a clinical trial setting to optimize success."

Using both types of research mice, Simeone and Pasca di Magliano are working together to identify the combination of mutant genes that drive the development of pancreatic cancer and figure out how to block their activity. Curing mice is one thing. Curing people will be much more difficult. But the two U-M scientists are cautiously optimistic.

"We have tumors directly from patients, and a mouse that gets a tumor in a step-wise manner just like a human patient does," says Pasca di Magliano. "In terms of a research model, this is as good as it gets."

It's a novel approach to finding more effective treatments for this deadly type of cancer. And it could mean that people with pancreatic cancer will finally have reasons to hope for a brighter future.

Mutant KRAS plus . . . "something else"

On a scale of one to 10, pancreatic cancer rates a 12 for aggressiveness and a one in terms of how well it responds to existing treatments. Unlike other types of cancer where early symptoms are obvious, the symptoms of pancreatic cancer abdominal discomfort, bloating and loss of appetite are vague and easy to ignore. Although researchers are searching for biomarkers to help diagnose pancreatic cancer early, there is nothing currently available.

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This article first appeared in the Spring, 2012 issue of Medicine at Michigan.