New research suggests that targeting a particular cell signaling pathway with the diabetes drug metformin might offer a way to stop the progression and spread of pancreatic cancer.

The study—which was led by Rutgers Cancer Institute of New Jersey in New Brunswick—is to feature at the 2018 annual meeting of the American Association for Cancer Research, which will be held in Chicago, IL.

This study is not the first to suggest metformin as a potential treatment for pancreatic cancer, but it is the first to show that the underlying mechanism involves the drug's effect on the REarranged during Transfection (RET) cell signaling pathway.

"Our data," says senior investigator XiangLin Tan, who is an assistant professor of epidemiology in the School of Public Health at Rutgers Cancer Institute of New Jersey, "indicate that targeting RET with metformin may be an attractive and novel strategy for the prevention and treatment of pancreatic cancer progression and metastasis."

Pancreatic cancer

Pancreatic cancer is a cancer that starts in the cells of the pancreas, which is an organ behind the stomach that helps with digestion and blood sugar control.

The estimates for the United States suggest that around 55,440 people will find out that they have pancreatic cancer in 2018, and approximately 44,330 people will die of the disease.

Though it is only responsible for 3% of all cancers in the US, pancreatic cancer accounts for around 7% of deaths from cancer.

Because pancreatic cancer is hard to detect in the early stages, most cases are not diagnosed until the disease has started to spread. This makes it harder to treat and often leaves people with much poorer prospects compared with other types of cancer.

Metformin and cancer

Metformin is a drug that is approved for the treatment of type 2 diabetes. The plant it comes from, the French lilac Galega officinalis, has been used to ease the symptoms of diabetes since the Middle Ages.

However, thanks to the evidence from extensive laboratory experiments and numerous studies that have followed large groups of people, there is now a lot of interest in the possibility that metformin might also be effective against cancer.

This interest has led to clinical trials that are testing metformin not only as a cancer treatment, but also as way to prevent cancer in people at higher risk, such as those who have already had one cancer and have a higher risk of developing another type.

Laboratory investigations have revealed several ways in which metformin interacts with cells and tissue that might explain its anti-cancer effects.

These studies revealed, for example, that the drug can target and kill cancer stem cells, control inflammation responses, and block a cell signaling pathway—called mammalian target of rapamycin—that plays an important role in tumor growth and progression.

None of these, however, have identified the specific mechanism by which metformin might act against pancreatic cancer.

Metformin and the RET signaling pathway

RET is a cell membrane receptor that sends and receives signals from the cell's environment. It is also an enzyme that becomes active when it binds to a particular molecule. Together, these roles make RET a key player in the control of cell proliferation, survival, and death.

Professor Tan and colleagues decided to investigate RET because the receptor and the molecule that it attaches to are strongly expressed in pancreatic cancer and are also linked to the spread of the cancer and worse survival after surgery.

In their experiments, they found that metformin reduced RET signaling in some pancreatic cancer cell lines.

The team also found that silencing RET by other means, as well as treatment with metformin, significantly reduced cell migration.

Therefore, the researchers conclude that blocking RET signaling is at least one of the mechanisms through which metformin stops the growth and spread of pancreatic cancer cells.

"Completion of this study will form the basis for developing a novel clinical intervention strategy for inhibiting the growth and spread of pancreatic cancer using metformin and/or other selective RET inhibitors."

Professor XiangLin Tan

The scientists call for further studies to identify the precise manner in which metformin alters RET signaling in pancreatic cancer.