In the process of looking for novel drug targets and new ways to disrupt disease-causing pathways for triple negative breast cancers (TNBC), researchers found that by repurposing two older drugs, metformin and heme, that are already in the marketplace, they may treat resistant breast cancers that currently have no targeted therapy.
And test of the two seasoned drugs in mice has produced encouraging results, according to a news release posted on the website of the University of Chicago on Monday.
Neither drug was designed to treat cancer. Metformin, discovered in 1922 and used clinically since 1957, was developed to treat type-2 diabetes. It decreases glucose production by the liver and increases insulin sensitivity.
The other drug, heme, marketed as panhematin, was first crystallized from blood in 1853. It is now used to treat defects of heme synthesis. These defects can cause porphyrias, a group of eight related ailments.
The researchers found that the primary anti-cancer target for heme is a transcription factor known as BACH1 (BTB and CNC homology1). This protein is often highly expressed in TNBC and is required for metastasis. High BACH1 levels often lead to poor outcomes.
BACH1 targets mitochondrial metabolism. It controls the rate of transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. This can suppress transcription of mitochondrial electron transport chain genes, a key source of cellular energy. When BACH1 is high, this energy source is shut down.
"We found we could basically put a thumb on this trouble-making BACH1 protein," said the study's senior author Marsha Rosner, a professor of the Ben May Department for Cancer Research at the University of Chicago. "We can get rid of it. It's part of a normal process."
"When cancer cells are treated with hemin, BACH1 is reduced, causing BACH1-depleted cancer cells to change metabolic pathways," said co-author Jiyoung Lee, an instructor affiliated with the Rosner laboratory. "This causes cancers that are vulnerable to metformin to suppress mitochondrial respiration. We found that this novel combination, hemin plus metformin, can suppress tumor growth, and we validated this in mouse tumor models."
"This is the first joint use of these two drugs. We think we have elucidated a new mechanism, something basic and fundamental, and found ways to use it," said Rosner.
The researchers also hold that the findings could extend beyond breast cancer. BACH1 expression is enriched not only in TNBC but is seen in many cancers, including lung, kidney, uterus, prostate and acute myeloid leukemia. BACH1 inhibition of mitochondrial electron transport chain genes appears to be a common mechanism.