Collaborative research carried out at the University of Dundee has suggested that the diabetes drug metformin may reduce the incidence of cancer. This has led to worldwide investigations into the use of metformin as a cancer preventative measure and the development of new drugs mirroring the effect of metformin.
In the late 1980s, Professor Grahame Hardie FRS at the University of Dundee provided key insights into the regulation, composition and downstream targets of an enzyme called AMP-activated protein kinase (AMPK). Prof Hardie established that this protein was an energy sensor in the body, making it a key target in studies of obesity, metabolism and diabetes.
In 2003, a major puzzle was the identity of the upstream regulator of AMPK. Also based at the University of Dundee and just along the corridor, Professor Dario Alessi FRS was working on a tumour suppressor protein called LKB1 and searching for its downstream targets. In many spontaneous cancers LKB1 is mutated, resulting in a loss of tumour suppressor function. Preliminary experiments soon led to the two researchers realizing that each held the solution to the other’s problem and, like fitting two halves of a jigsaw together, they discovered that AMPK was activated and controlled by LKB1. This provided a link between a key regulator of cellular metabolism (AMPK) and a protein involved in cell proliferation and cancer (LKB1). When LKB1 function lost, it is no longer able to activate AMPK, resulting in increased tumour formation by removing the restraining influence that this pathway has on cell growth and proliferation.
The link between AMPK and LKB1 was intriguing, since it was already known that the drug metformin, already in use to treat type-2 diabetes, activated AMPK. Collaborative research between Professors Alessi and Andrew Morris FRSE FMedSci (Professor of Diabetic Medicine at the University of Dundee) went on to test the hypothesis that metformin could decrease the incidence of cancer by activating AMPK. Results of the subsequent epidemiological study showed that people with diabetes taking metformin were 30% less likely to develop any form of cancer than those on other medications.
This work has had a major impact on the cancer field, especially as metformin is orally available, has no long-term safety issues and is available as a generic drug. This has led to at least 52 case-controlled clinical trials worldwide examining the effect of metformin in a variety of cancers such as pancreatic, prostate, colorectal, and breast cancer. These kinds of trials will establish whether the stratification of patients with AMPK-inactivation in their cancers will benefit from AMPK-activating drugs. This knowledge has also led to several drug discovery campaigns to develop novel activators of this pathway, for the treatment of both diabetes and cancer.