"About 29,000 cases of pancreatic cancer are diagnosed yearly in the United States," observed cancer geneticist Ronald DePinho at Harvard-affiliated Dana Farber Institute. "And all but 100 or 200 of those individuals succumb within a year. Pancreatic is the most lethal of human cancers. And often times when patients are diagnosed with the disease, [it is in advanced stages]. The major unmet needs are the ability to detect the disease early when the cancer might be more amenable to surgical cure or therapy. The second need is to develop therapies that actually impact on survival. Virtually no therapeutic modalities have had success on the survival statistics of these pancreatic cancer patients."
DePinho is senior author of a paper in Genes & Development (published by Cold Spring Harbor Press) dated Dec. 15, 2003. Its title: "Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma in the mouse." The article's lead author is Nabeel Bardeesy, who noted 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 human patients."
"In addition," DePinho added, "it supplies us with a chance to layer in mutations, such as p53, that are seen in the disease. We ascertained the specific tumor biological contributions that such mutations have in the disease. Do they make the cancer more malignant or metastatic? More resistant to therapy? And so on. Now that we've gotten this important first step, we have a faithful animal model on which we can better understand genotype-phenotype correlations.
"One thing at the top of the list for a major need in the field," DePinho pointed out, "is development of a mouse model that faithfully recapitulates the evolution of pancreatic ductal adenocarcinoma, but on genetic lesions that are classical for that disease. Virtually all of the animals have highly malignant disease by 6 to 8 weeks of age," he continued. "And by 11 weeks of age, 100 percent of the animals succumb to the cancer. All die between 7 and 11 weeks of age, which provides a nice window in which to test existing therapies and therapeutic combinations."
DePinho said, "This model will allow us to test chemo-preventive agents to see if we can delay the onset of the disease. If we exposed these mice to tobacco smoke [a risk factor], or to specific diets, for example, it might provide us with opportunities to more rigorously define the contributions of those dietary and environmental factors to development of the disease. I think there have been about 15 years of effort in the field to develop a mouse model for what is one of the major cancer killers. And we've now succeeded. I think [the mice] are important because of the social, economic and health toll that any particular cancer type has on human populations. So at the top of the list would be lung cancer, and then, moving on down, pancreatic cancer at fourth as the top cancer killer.
No Extant Therapy Can Impact Pancreatic Survival
"The present form of therapy," DePinho said, "if the disease is reasonably contained, is surgery, but there is no therapy that currently exists that impacts on the survival of the pancreatic cancer patients. There is an antitumor drug called gemcitabine, which simply has improved their quality of life. The typical symptomatic pattern of the disease in its evolving form is part of the problem. The patients typically present with a little bit of indigestion, fullness, a little heart burn, some weakness - very nonspecific symptoms. And the tumor grows without creating any problem unless it's very close to the bile duct, in which case he or she gets jaundice from biliary obstruction. But typically the tumor grows to be baseball size before anything is really significantly wrong with the patients. They develop these nonspecific symptoms, but then once the disease really takes off and the patients are diagnosed, they have only a few more months to live.
"As for new therapeutics in the offing, anti-angiogenesis factors may figure prominently in pancreatic cancer treatment - depriving the tumor of its blood supply. That's going to be an important one, so we should look for that. We have a ways to go," DePinho said, "but anti-angiogenesis is likely to be the next major therapeutic opportunity.
"Many, many dozens of clinical trials in pancreatic cancer have had no effect. For some reason this disease is extremely resistant to chemotherapy and radiotherapy. So having a mouse model will give us some insights into why the tumors are so resistant.
"We contemplate human clinical trials ultimately," DePinho allowed. "They're being conducted at the Dana-Farber and other cancer institutes. We would use these mice obviously in a preclinical phase of testing those drugs. Our research findings lend themselves to patenting," he volunteered. "They cover the characteristics of these mice for use in preclinical experimental therapeutics and biomarkers. A patent-application disclosure has already been filed, but we have no commercial partner as yet. We're very interested in working with corporate entities.
"There is an increasing awareness," DePinho went on, "that genetically engineered mouse models provide more accurate and penetrating information on human disease. And there is increasing attention in the industry for those interested in anticancer drug development in particular," he concluded, "to exploit the experimental merits of these mouse models."