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New Drug Combination for Triple-Negative Breast Cancer

Breast cancer.

Triple-negative breast cancer (TNBC) accounts for approximately 10% to 20% of all breast cancers. Whereas therapies targeting the estrogen receptor, the progesterone receptor, and the human epidermal growth factor receptor 2 have demonstrated efficacy in other breast cancer subtypes, women with TNBC cancer lack these treatment targets because their cancer does not have any of these three receptors. Patients with TNBC are instead typically treated with standard chemotherapy, which does not always prove to be effective. In their search for an effective treatment option for TNBC, researchers at the University of Chicago discovered that two older drugs, metformin and hemin, work together to kill TNBC in mouse models.

"We think we may have found a way to treat resistant breast cancers that currently have no targeted therapy by repurposing two older drugs, metformin and hemin that are already in the marketplace," remarked the study's senior author, Marsha Rosner, PhD, the Charles B. Huggins Professor in the Ben May Department for Cancer Research at the University of Chicago. "To our knowledge, 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."

Metformin, a drug used to treat type 2 diabetes by decreasing glucose production and increasing insulin sensitivity, was not designed to treat cancer; however, patients with type 2 diabetes prescribed metformin are less likely to develop cancer due to the drug's ability to stop the growth of cancerous cells. The second drug, hemin (Panhematin®, Recordati Rare Diseases Inc.) is used to treat defects of heme synthesis—the process by which heme is produced.

The investigators discovered that hemin targets BTB and CNC homology 1 (BACH1), a transcription factor that is usually expressed in TNBC and is necessary for metastasis. This regulator protein binds to a certain DNA sequence in order to target mitochondrial metabolism and control the rate of transcription of genetic information from DNA to messenger RNA, with the result of hindering transcription of mitochondrial electron transport chain genes.

"When cancer cells are treated with hemin, BACH1 is reduced, causing BACH1-depleted cancer cells to change metabolic pathways," commented the study's lead author, Jiyoung Lee, PhD, an instructor affiliated with Dr. Rosner's 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 research paves the way for further research targeting BACH1, which is present not only in TNBC but also in acute myeloid leukemia and in lung, kidney, uterine, and prostate cancers.

"Our results highlight BACH1 as a key regulator of mitochondrial metabolism and a determinant of TNBC response to metformin treatment," the researchers stated in their study, which was published in Nature. "The role of BACH1 as a novel regulator of metabolism has not previously been recognized or studied. This study will open new avenues for future investigation."

For More Information

Lee Y, Yesilkanal AE, Wynne JP, et al (2019). Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature. [Epub ahead of print] DOI:10.1038/s41586-019-1005-x

Image courtesy of Yale Rosen

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