Repurposed Diabetes Drug Shows Promise as Breast Cancer Treatment
Epalrestat could prevent metastasis in patients with basal-like triple-negative breast cancer.
Repurposing drugs can provide patients with expedited access to treatment, since the safety profile is already known and can speed a supplemental approval. Investigators have long been looking into repurposing drugs to improve options for patients with hard-to-treat cancers and other diseases.
An approved diabetes drug may be able to prevent metastasis in patients with aggressive, basal-like triple-negative breast cancer, according to a study published by The Journal of Experimental Medicine.
In the study, the authors discovered that the enzyme AKR1B1 drives basal-like breast cancer, which accounts for 15% to 20% of all cases of the disease. This subtype is particularly aggressive, and tends to recur and metastasize to the brain and lungs early after initial treatment. Since there are no targeted treatments, this form of breast cancer has a poor prognosis.
Basal-like breast cancer utilizes epithelial-mesenchymal transition (EMT), which allows cells to become mobile and more stem cell-like. EMT facilitates treatment resistance, and tumor growth in other tissues, according to the study.
The authors discovered that basal-like triple-negative breast cancers had high levels of AKR1B1 expression, which was linked to high rates of metastasis and poor patient outcomes. Upon further investigation, the authors found that increased AKR1B1 expression was induced by the cellular transcription factor Twist2, which is involved with EMT.
Then, AKR1B1 increased Twist2 levels through producing the prostaglandin F2 lipid, which activates the NF-B signaling pathway. This AKR1B1-Twist2 feedback loop was observed to be critical for the cancer cells to undergo EMT, according to the study.
The researchers found that lowering AKR1B1 levels inhibited the cells from metastasizing or taking on stem cell-like qualities. Lower AKR1B1 levels were also observed to prevent tumor growth and metastasis in mice models of basal-like breast cancer.
“Our data clearly suggests that AKR1B1 overexpression represents an oncogenic event that is responsible for the aggressive behaviors of basal-like breast cancer cells," said researcher Chenfang Dong, PhD, MD.
Perhaps their most significant finding, the authors observed that a drug approved in Japan to treat a diabetes complication was able to inhibit cancer growth and metastasis of human basal-like triple-negative breast cancer cells.
The drug, epalrestat, is an AKR1B1 inhibitor approved to treat patients with peripheral neuropathies associated with diabetes. If confirmed in additional human studies, the drug could be offered to patients with basal-like breast cancer on an expedited pathway.
"Since epalrestat is already on the market and has no major adverse side effects, our study provides a proof of principle that it could become a valuable targeted drug for the clinical treatment of basal-like breast cancer," Dr Dong concluded.