Uridine discovery could lead to new pancreatic cancer therapies

Pancreatic cancer

Pancreatic cancer cells can change their ‘diet’ to keep growing, by switching from the sugar glucose to a back-up fuel called uridine, new research has revealed.

The findings suggest that blocking the availability of uridine using new drugs could become a new treatment strategy for the most common and aggressive form of pancreatic cancer.

The researchers believe uridine could help fuel other cancers too – such as lung, stomach and brain cancer.

The study was led by scientists at The Institute of Cancer Research, London, and the University of Michigan in the US.

The molecule uridine is essential for a healthy metabolism. But researchers found that uridine, which is present in the tumour microenvironment, also serves as a food source for pancreatic cancer when glucose is scarce. Taking advantage of uridine in this way allows cancer cells to keep growing even when their usual food source is unavailable.

Using phenotypic microarray researchers screened for nutrients used by pancreatic cancer cells over time, taking readouts every few minutes over three days. They found that uridine is broken down by enzyme uridine phosphorylase-1 (UPP1) to produce a different form of sugar, ribose, which can fuel cancer cells.

Knocking out the UPP1 gene in mice stopped pancreatic cancer cells from using uridine and halted tumour growth.

Professor Kristian Helin, Chief Executive of the ICR, said: “We know cancer cells use different metabolic pathways to obtain nutrients that allow them to survive and keep growing. It is exciting that this new study has found that pancreatic cancers can switch their diets and may become dependent on a particular back-up fuel. We hope we can take advantage of this finding about the underlying biology of pancreatic cancers to find ways to treat the disease more effectively, including through use of existing drugs.”

New treatment strategies

The team also looked at patient samples and found that high levels of UPP1 were linked to poor survival in people with pancreatic cancer, as well as other cancer types – suggesting that uridine may also help feed other cancers.

Researchers found that levels of UPP1 are boosted in the presence of KRAS-MAPK signalling, a type of cell signalling that promotes the growth of many cancer types, particularly pancreatic cancer. This led them to believe that drugs which block KRAS signalling might also block uridine availability, cutting off cancer’s emergency food supply.

There are no approved drugs for use in humans which block UPP1, but some KRAS inhibitors have already reached the clinic, and researchers will work to develop new UPP1 inhibitors.

Study co-leader Dr Anguraj Sadanandam, Team Leader in Systems and Precision Cancer Medicine at The Institute of Cancer Research, London, said: “Cancer cells salvage anything available in their environment and use it for their own benefit. We have found that the deadliest form of pancreatic cancer can even change its diet in order to survive.

“Next, we will explore ways to use uridine to monitor existing therapy responses in pancreatic cancer and hopefully develop new drugs targeting UPP1. We hope our research efforts will lead to new treatment strategies for people diagnosed with pancreatic cancer.”

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