New Study Changes Understanding of Pancreatic Cancer
A dense mixture of cells and proteins that typically surrounds pancreatic cancer is thought to protect and nourish the tumor, but research from the Herbert Irving Comprehensive Cancer Center shows that some elements of the mixture fight the malignancy.
The findings also explain why one drug designed to dissolve the mixture, called stroma, failed in recent clinical trials. The study was published in the June 16 issue of Cancer Cell.
Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is notorious for the amount and density of its stroma. Stroma can make up 90 percent of the mass of pancreatic cancers and is thought to be a key factor in the tumor’s tenacity. Because the stroma prevents chemotherapy drugs from reaching malignant cells, numerous therapies that dissolve it are currently in development.
One such drug was based on previous research by Kenneth Olive, PhD, professor of medicine and pathology. He found that by blocking a particular pathway that drives the formation of stroma, some of the stroma dissolved, more chemo reached the tumor, and survival improved in mice with pancreatic cancer.
But when the drug was tested in people, the trial was unsuccessful.
Olive and his colleague Paul Oberstein, MD, assistant professor of medicine, set out to discover what went wrong. “Every clinical trial that fails is a tragedy, but it’s a greater tragedy if you don’t learn anything in the process,” Olive says.
The two researchers realized that while the patients had received treatment for a few months, the mice had received treatment only for a few weeks. (To mimic the typical human scenario, mice were not treated until their tumors were large and the mice had only a short time before succumbing).
In the current study, mice received longer courses of treatment, starting early on. The authors were surprised to find that using the same drug in the same type of mice in a different way produced the opposite result: Mice treated with the drug succumbed sooner to their tumors.
When they looked at the tumors under a microscope, the researchers found that tumors had less stroma, but it was more aggressive and made the mice sicker.
In work done with collaborators at Penn and the University of Michigan, tumors of the same type were seen in a strain of mice that lacked the stroma-promoting pathway, demonstrating that the finding was not due to an unknown side effect of the drug.
“What we’ve found is that, counter to most current thinking, there are some stroma elements that are slowing down the tumor,” Olive says.
“Many trials are now targeting stroma. Undoubtedly, there are some elements that make good targets—but there are some elements that are not good targets. We should understand these elements in more depth, before we start large-scale clinical trials.”