Research sheds new light on why pancreatic cancer drugs fail

An international team of scientists, led by researchers based at the Cambridge Research Institute, have discovered a new mechanism that may explain why pancreatic cancer patients are often resistant to a common chemotherapy treatment, germcitabine.

The study, published in the journal Science today, shows that a genetically modified mouse model of pancreatic cancer, which closely resembles human cancer, is largely resistant to germcitabine treatment. It is hoped that these results will help scientists overcome a common resistance to germcitabine and make future chemotherapy drugs more effective.

The scientists had set out to discover why promising drugs generally fail in pancreatic cancer clinical trials. They found that in these mice studies pancreatic cancer is resistant to chemotherapy because the tumours tend to have poor networks of blood vessels called vasculature, which makes it harder for drugs to reach the tumour.

Working with groups at Addenbrooke’s Hospital, the Johns Hopkins Hospital, the University of Dresden, MD Anderson Cancer Centre, University of Pittsburgh and the Fred Hutchison Cancer Research Centre, they also noted that human pancreatic cancer samples also contained a deficient blood supply, suggesting that their observation should also be applicable to patients.

Senior author Dr David Tuveson, group leader in tumour modeling and experimental medicine at Cancer Research UK’s Cambridge Research Institute, said: “We’re extremely excited by these results as they may help explain the disappointing response that many pancreatic cancer patients receive from chemotherapy drugs.”

The study also found that the genetically modified mice displayed the same resistance to gemcitabine as seen in human pancreatic 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.

When the scientists added the compound called IPI-926, created by Infinity Pharmaceuticals, to gemcitabine, they noticed increased cell death and a reduction of the pancreatic tumour size. Using this combination the researcher believe that it could 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.

“But these are early days and we need to show this approach is safe to use in humans before we can consider adding the new compound to cancer treatments,” said Dr Tuveson.

These findings may also help to explain why pancreatic 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 tumour by restricting its blood supply. As pancreatic cancers don’t seem to need as good a supply of blood to the tumour as other cancers, the scientists believe that they may need to introduce additional drugs to help stop tumour growth.

The scientists at Cancer Research UK’s Cambridge Research Institute were co-funded by The Lustgarten Foundation and the National Institutes of Health.

The Cancer Research UK Cambridge Research Institute is a major new research centre which aims to take the scientific strengths of Cambridge to practical application for the benefit of cancer patients. The Institute is a unique partnership between the University of Cambridge and Cancer Research UK. It is housed in the Li Ka Shing Centre, a state-of-the-art research facility located on the Cambridge Biomedical Campus which was generously funded by Hutchison Whampoa Ltd, Cambridge University, Cancer Research UK, The Atlantic Philanthropies and a range of other donors. For more information visit www.cambridgecancer.org.uk.