Scientists shed new light on why pancreatic cancer drugs can fail

Cancer Research UK scientists led an international team of investigators who have discovered a new mechanism that may explain why pancreatic cancer patients are often resistant to a common chemotherapy treatment called gemcitabine*, according to a study published in Science**.

It is hoped this study will help scientists overcome a common resistance to gemcitabine and make future chemotherapy drugs more effective.

Pancreatic cancer is diagnosed in 230,000 people across the world***, with 7,600 new cases in the UK and 37,000 new cases in the United States each year. Only three per cent of patients survive for five years or more.

The scientists at Cancer Research UK's Cambridge Research Institute - who were co-funded by The Lustgarten Foundation and the National Institutes of Health, sought to understand why promising drugs generally fail in pancreatic cancer clinical trials. They found that a genetically modified mouse model of pancreatic cancer that closely resembles human cancer was also largely resistant to gemcitabine treatment.

The scientists found in these mouse studies that 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 Dresden the MD Anderson Cancer Centre, University of Pittsburgh and the Fred Hutchison Cancer Research Centre, the group 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 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 pancreatic tumour 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.

"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.

Kerri Kaplan, executive director of The Lustgarten Foundation, the largest private funder of pancreatic cancer research in the United States, said: "Because pancreatic cancer is so difficult to treat with standard chemotherapy, these study results demonstrate progress toward greater understanding of how to treat this swift, silent and deadly disease. The Foundation remains committed to supporting research that improves our understanding of pancreatic cancer, in the hope that one day, early diagnostic tools and new, improved treatments can be found."

Dr Lesley Walker, Cancer Research UK's director of cancer information said: "This is a very substantial finding. If these results hold in future studies, we hope that scientists will be able to make better use of current treatments and develop a range of new options which will help people with pancreatic cancer live longer.

"Cancer Research UK's five year strategy highlights the importance of targeting areas of unmet medical need, such as pancreatic cancer, so we can have the greatest impact on reducing cancer deaths in the future. Results like these give us real confidence that we will combine this focus with our other research efforts and meet our goals of improving survival from all forms of the disease."

*This study used gemcitabine (Gemzar) which is one of a group of chemotherapy drugs called anti-metabolites. Anti-metabolites are similar to normal body molecules but they are slightly different in structure. These differences mean that anti-metabolites stop cells making DNA. Cancer cells need DNA to multiply. You can find out more about this drug and other treatments for pancreatic cancer on Cancer Research UK's patient information website CancerHelp UK

**Inhibition of Hedgehog Signalling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer. Science. May 2009. Kenneth P. Olive et al.

***Estimates show 230,000 people across the world were diagnosed with pancreatic cancer in 2002.

****IPI-926 is novel, selective, potent, small molecule Hh pathway inhibitor that directly blocks the activity of Smoothened (Smo). It is currently being investigated in a Phase 1 clinical trial by Infinity Pharmaceuticals. Because Smo plays a critical role in the malignant activation of the Hh pathway, Smo may be a target for the management of a broad range of cancers.