Novel, Repurposed Drug Combo Shows Potential in Triple-Negative Breast Cancer

In triple-negative breast cancer (TNBC), patients are often limited to treatment with standard chemotherapy due to the lack of therapeutic targets. However, new research has pinpointed 2 older drugs already on the market for different uses that may work together to treat resistant TNBC. 
The study, published in Nature, found that repurposing drugs metformin and heme, marketed as panhematin, produced promising results when tested in mice. Metformin, a widely used type 2 diabetes treatment, works by decreasing glucose production by the liver and increasing insulin sensitivity. Patients with diabetes who take metformin are less likely to develop cancer due to its direct anti-cancer effect involved in repressing the proliferation of tumor cells, according to the study.
Previous studies have also indicated a therapeutic effect for metformin in cancer. For example, the drug combination metformin and venetoclax has been studied in breast cancer animal models, as well.
The second drug, heme, is currently used to treat defects of heme synthesis. When combined, the researchers said that these 2 drugs could suppress tumor growth in mouse tumor models.
“To our knowledge, this is the first joint use of these 2 drugs,” senior study author Marsha Rosner, Charles B. Huggins professor in the Ben May Department for Cancer Research at the University of Chicago, said in a press release. “We think we have elucidated a new mechanism, something basic and fundamental, and found ways to use it.”
According to the researchers, they identified the primary anti-cancer target for heme as a transcription factor known as BTB and CNC homology1 (BACH1), a protein often highly expressed in TNBC. High BACH1 levels can lead to poor outcomes because the protein is a key regulator of mitochondrial metabolism. According to the study, BACH1 also serves as a determinant of TNBC response to metformin treatment.  
Using heme, the researchers found that they could reduce BACH1, causing BACH1-depleted cancer cells to switch metabolic pathways. The study showed that BACH1 depletion due to hemin sensitizes cells to treatment with metformin.
“This causes cancers that are vulnerable to metformin suppress mitochondrial respiration,” study co-author Jiyoung Lee, an instructor affiliated with the Rosner Laboratory, said in the press release. “We found that this novel combination, hemin plus metformin, can suppress tumor growth, and we validated this in mouse tumor models.”
The researchers concluded that the findings support the concept that mitochondrial metabolism can be exploited by targeting the BACH1 protein to sensitize TNBC and potentially other tumor issues to mitochondrial inhibitors, according to the study.
Lee J, Yesilkanal AE, Wynne JP, et al. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature. Published March 6, 2019. Accessed March 12, 2019.
Medicines for diabetes, blood disorders show promise for triple negative cancers [news release]. University of Chicago. Accessed March 12, 2019.

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