Scientists have discovered a biomarker that shows which cancer cells are vulnerable to destruction with a class of drugs used to treat diabetes.
It has been known for a while that biguanides, which include the common type 2 diabetes medication metformin, have anticancer properties and can stop the growth of some cancer cells by dramatically reducing or stopping their cellular metabolism.
Biguanides have been around for a long time. They are primarily known for their ability to lower blood sugar, and metformin, now one of the most commonly prescribed medications in the USA, has been available to treat diabetes since the 1950’s.
However, attempts to apply this anti-cancer property have been disappointing. It is difficult to get enough of the active agent into cancer cells to be effective. Also, not all cancers respond to these drugs and there has not been an easy way to find out which ones are most likely to be sensitive to them.
“Cancers vary widely in how they react to different therapies — what works for one cancer type may not work for another — but regardless, they are all reliant on metabolism for energy production,” said Russell Jones, PhD, a professor at Van Andel Research Institute in Michigan, USA, who was one of the lead researchers for the study.
As published in the journal Cell Reports Medicine, Jones and co-researchers discovered that the cancer-associated gene MYC plays a big role. MYC is overexpressed in up to 70% of lymphomas and promotes cancer growth by increasing cancer cell metabolic activity, while simultaneously reducing the expression of genes that supress cancer.
Although MYC helps cancer cells to replicate, it also makes them more vulnerable to stress and this is where biguanides come in. The scientists tested two drugs in this class – phenformin and a new biguanide developed by the US biotech Immunomet Therapeutics – in lymphoma cells. They found that lymphoma cells that were positive for MYC expression and that were also expressing a specific microRNA called miR-17∼92 were vulnerable to destruction by the drugs, which died due to metabolic stress.
“Our results establish two important things,” commented Jones. “First, they give us a way to objectively determine which types of cancer are sensitive to biguanide treatment and, second, they illuminate how and why some patients may respond better to biguanides than other patients.”
The results suggest that despite disappointing results in the past, the knowledge of the MYC-linked miRNA biomarker could help researchers and biotech’s such as Immunomet develop targeted biguanides to treat cancer.
It is likely that new drugs in the class, such as Immunomet’s candidate drug, will need to be developed to do this. Metformin is safe, but not absorbed in high enough doses to be effective against cancer. Other biguanides such as phenformin, which have greater absorption and anti-cancer potential than metformin, come with high risks of side effects. Most notably, lactic acidosis – an issue that caused both phenformin and another drug in the class buformin to be withdrawn from the market for treating diabetes.
So far Immunomet’s lead biguanide has not demonstrated significant safety concerns in Phase I testing, but it remains to be seen if it will reach the market successfully.