Why pancreatic-cancer drugs can fail

An international team of investigators, led by Cancer Research UK scientists and including the Hutchinson Center's Dr. Sunil Hingorani, have discovered a mechanism that may explain why pancreas-cancer patients are often resistant to a common chemotherapy treatment called gemcitabine.

It is hoped the study, published last week in Science, will help scientists overcome a common resistance to gemcitabine and make future chemotherapy drugs more effective.

Pancreas cancer is diagnosed in 230,000 people across the world, with 37,000 new cases in the U.S. each year. Only 3 percent of patients survive for five years or more.

The scientists at Cancer Research UK’s Cambridge Research Institute sought to understand why promising drugs generally fail in pancreas-cancer clinical trials. They found that a genetically modified mouse model of pancreas cancer that closely resembles human cancer was also largely resistant to gemcitabine treatment.

Hingorani of the Center’s Clinical Research Division, and director of the Pancreas Cancer Specialty Clinic at the Seattle Cancer Care Alliance, co-developed the mouse model used in the study. He also helped design the initial study and his lab helped characterize the tumor vasculature—the density and distribution of blood vessels in these tumors—and how that may serve to impede the delivery of chemotherapy to the tumor cells.

The scientists found in these mouse studies that pancreas cancer is resistant to chemotherapy because the tumors tend to have poor networks of blood vessels, which makes it harder for drugs to reach the tumor. Working with groups at Addenbrooke’s Hospital, the Johns Hopkins Hospital, the University of Dresden, MD Anderson Cancer Center and the University of Pittsburgh, the research team also noted that human pancreas-cancer samples also contained a deficient blood supply, suggesting that their observation should also be applicable to patients.

The study also found that the genetically modified mice displayed the same resistance to gemcitabine as seen in human pancreas cancer, whereas the transplantation mouse models traditionally used to develop chemotherapy treatments were sensitive to gemcitabine. This means that the new genetically modified models could prove superior in developing new treatments in the future.

“This study reveals a perhaps unappreciated or underappreciated mechanism of resistance of pancreas cancer to chemotherapy and a way to overcome that resistance,” Hingorani said. “This approach could potentially be a very important part of the way we treat this disease in the future.”
 
Senior author Dr. David Tuveson, group leader in tumor modeling and experimental medicine at Cancer Research UK said, “We’re extremely excited by these results as they may help explain the disappointing response that many pancreas-cancer patients receive from chemotherapy drugs.” 

When the scientists used a new compound called IPI-926, which was created by Infinity Pharmaceuticals, in combination with gemcitabine in the genetically modified animals, they noticed increased cell death and a reduction of the pancreas-tumor size. They believe that using this combination may also re-open the door to several new treatments which have, so far, proven disappointing in patient trials for pancreatic cancer because of poor drug delivery.

These findings may also help to explain why pancreas cancer does not respond to anti-angiogenic drugs such as VEGF inhibitors when many other cancers do. These are a new class of drugs which starve the tumor by restricting its blood supply. As pancreas cancers don't seem to need as good a supply of blood to the tumor as other cancers, the scientists believe that they may need to introduce additional drugs to help stop tumor growth.

[Story adapted from a Cancer Research UK news release.]