A new, bioengineered strain of mice has the 2 signature mutations associated with development of pancreatic ductal adenocarcinoma in humans, according to an article in the December 15th issue of Genes and Development.

Because the mouse-model tumors start and progress along a path that closely resembles the course of disease in humans, the researchers believe the mice will be useful in identifying possible biomarkers that could be used to develop a blood or urine screening test. The value of early diagnosis is high because patients are typically diagnosed at a late stage and the tumors are usually resistant to chemotherapy and radiation. Currently, nearly all of the 30,000 annual U.S. cases are fatal within a matter of months.

"This model shows great promise as a platform for rapid and efficient testing of novel therapeutic agents and for the discovery of tumor stage-specific markers - both critical, unmet needs for the fourth-leading cause of cancer death in the United States," said Ronald A. DePinho, M.D., senior author of the paper.

As in other solid tumors such as colon cancer, a series of mutations underlies the conversion of normal cells in the pancreatic ducts to a precancerous series of stages termed PanIN-1, 2 and 3, and, finally, invasive adenocarcinoma. Only adenocarcinomas are associated with the development of jaundice and symptoms of pain, nausea, and weight loss, which prompt testing and diagnosis.

The signature genes for carcinogenesis seem to be Kras and Ink4a/Arf, and the responsible mutations were successfully introduced into the mice. The combination of expression of the mutant KrasG12D allele and deletion of the possible tumor suppressor gene Ink4a/Arf result in early development in mice of precancerous lesions with rapid progression to invasive and metastatic cancer.

Nabil Bardeesy, PhD, a coauthor of the study, said that because the cancer-prone mice are all genetically identical and raised in a standard environment, it is possible to identify the biomarkers associated with early and late stages of the cancer. This will provide an entry point for the discovery of equivalent molecules useful in screening humans.