Triple-negative breast cancer patients lack three common markers—estrogen, progesterone and HER2—making them unresponsive to targeted therapies. A team led by University of Chicago scientists may have found a new option for these patients, and it's one that involves combining two old FDA-approved drugs for diabetes and porphyria, a rare disorder marked by a lack of heme, a substance in blood that's essential for oxygen transport.
The drugs are metformin, a widely prescribed Type 2 diabetes medication that has been clinically used since 1957, and hemin, which has been marketed as panhematin to treat porphyria. Studies using cell lines and mouse tumor models showed that the novel combination can suppress triple-negative breast tumor growth, according to a paper published in the journal Nature.
Scientists have previously shown that patients taking metformin tend to have a lower risk of developing cancer. Although there isn't a strong consensus as to why that is, one popular view is that metformin inhibits a subgroup of the mitochondrial electron transport chain (ETC)—a series of complexes that are key in cell metabolism. Without that ETC, cancer cells lack the energy source they need to grow.
Using bioinformatics tools, the University of Chicago-led team showed that a transcription factor called BACH1 is crucial for the spread of aggressive triple-negative breast cancers and is associated with poor outcomes. BACH1 can suppress the transcription of ETC genes, the researchers found. When BACH1 is over-produced, cancer cells tend to shift their metabolic pathways. Yet when BACH1 is knocked out in mice, it doesn’t affect their growth, “which suggests that BACH1 may be a good target for cancer therapy because it controls cellular stress responses but is not essential—and therefore may be inhibited with few side effects,” the authors wrote in their study.
Heme inhibits BACH1, and in so doing, it sensitizes triple-negative breast tumors to become susceptible to metformin as tumor cells return to the pathway that can be targeted by the diabetes drug, according to the team.
“We found we could basically put a thumb on this trouble-making BACH1 protein,” Marsha Rosner, the study’s senior author, said in a statement. “We can get rid of it. We can do that with heme. It’s part of a normal process.”
Joseph Wynne, a clinical fellow in Rosner’s lab, argued that their findings hold promise for three populations of triple-negative patients. In patients with low BACH1 and high mitochondrial gene expression, metformin alone could work, Wynne said in the statement. For patients with high BACH1 and low mitochondrial gene expression, adding heme might be useful. And for patients who are “somewhere in between,” the researchers anticipate the combo would also work well.
Moreover, the findings could extend beyond breast cancer, the authors noted, as “BACH1 mRNA expression is enriched not only in breast cancer, but also in many other types of cancer including lung, kidney, uterine and prostate cancer and acute myeloid leukemia.”