June 1, 2001

Mouse models crucial in fighting pancreatic cancer

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Christopher Wright, D. Phil., speaks at a NCI/VICC sponsored symposium held at Loews Vanderbilt Plaza last week. Wright led the discussion on embryonic pancreatic development. (photo by Dana Johnson)

Mouse models crucial in fighting pancreatic cancer

Pancreatic cancer, the deadliest of all malignancies, is a complex disease involving a wide range of genetic abnormalities.

Mouse models of human pancreatic cancer are greatly needed to understand these genetic complexities before they can be exploited for earlier detection or targeted therapies, participants at a Mouse Models of Pancreatic Cancer Symposium were told last week.

“If there’s any doubt that mouse models are needed, look at the statistics,” said Dr. Dan Longnecker, professor of Pathology at Dartmouth Medical School and opening speaker. “When you consider both genders, pancreatic cancer is the fifth leading cause of cancer death.”

An estimated 29,000 Americans will be diagnosed with pancreatic cancer this year; almost that many will die of the disease. Because it often has no symptoms, pancreatic cancer is typically diagnosed only at advanced stages. Only 4 percent of patients are alive five years after diagnosis.

The two-day symposium, co-sponsored by the Vanderbilt-Ingram Cancer Center and the National Cancer Institute, drew more than 100 participants from across the United States, Canada, Japan, the United Kingdom, Germany, Sweden and Korea.

Participants heard from 20 speakers on topics ranging from pancreatic development in the embryo to transgenic targeting of nuclear transcription factors. In addition to oral presentations, more than a dozen posters were also presented.

The event at Loews Vanderbilt Plaza on May 24-25 was co-directed by Dr. Robert Coffey, Ingram Professor of Cancer Research at VICC, and Dr. Steven Leach, a former Vanderbilt-Ingram researcher who is now the Paul K. Newmann Professor in Pancreatic Cancer at Johns Hopkins University. Hopkins has a very large and respected pancreatic cancer program.

The genes involved in pancreatic cancer were only first identified in the 1980s, starting with the first oncogene in 1985 and the first tumor suppressor gene in 1987, Longnecker said. The mutation in the gene known as k-ras, implicated in about 90 percent of pancreatic cancer cases, was identified in 1988. This gene is important in the signaling between cells that leads to cancer.

Other genes involved in pancreatic cancer include transforming growth factors alpha and beta, the epidermal growth factor and its receptor, and tumor suppressor genes p16, p53, DPC4 and BRCA2.

In most cases, multiple genes are involved, Longnecker said, noting a study by a group of Hopkins scientists involving 42 cases – nearly 80 percent of which involved either four or three different genetic mutations. Only 8 percent of cases involved a mutation in k-ras alone.

Vanderbilt-Ingram Cancer Center is a participant in the NCI’s Mouse Models of Human Cancer Consortium, an initiative to promote development of models for cancer research. That effort at Vanderbilt-Ingram includes collaborative work to identify mouse models for pancreatic cancer as well as other malignancies.

Christopher Wright, D. Phil., professor of Cell Biology, outlined work by him and his colleagues to identify a “cell of origin” for pancreatic cancer. The group has found a gene, pdx1, which is important in early development of the pancreas, and is also reactivated in early pancreatic tumor formation.

Wright told the audience that their studies have demonstrated that inactivation of the pdx1 gene prevents a proliferative response to growth signals and thus prevents pancreatic development. They also have demonstrated that inappropriate reactivation of pdx1 leads to cell proliferation.

“The question is does ‘pancreas development equal regeneration equal cancer?’” Wright asked. “More knowledge is needed, including how cells choose and commit irreversibly to pathways (leading to differentiation) and a more precise definition of cell types.”

The event was also supported by the American Digestive Health Foundation, the American Gastroenterology Association, DuPont, the National Institutes of Health Office of Rare Diseases, Park Davis and Wyeth Ayerst.