The match game

KANNAPOLIS, N.C.—Mixing and matching or repurposing drugs developed for one disease to treat another is nothing new, but Dr. Xiaohe Yang, senior researcher and associate professor at North Carolina Central University (NCCU), may have come up with an ideal match. Yang has discovered that well-known drugs for type 2 diabetes—along with a dietary component—could be the key to the prevention of triple-negative breast cancer (TNBC) and other specific breast cancer subtypes.

“Repurposing of drugs is growing more and more common among researchers today,” Yang tells DDNews. “The safety profiles of these drugs are already established. Novel applications of the drugs with a known safety profile and low cost—like the case of metformin—are attractive strategies to achieve maximum benefits from these previously FDA-approved drugs.”

Yang’s research has broadened the understanding of the anticancer mechanisms of metformin and buformin, drugs once developed for type 2 diabetes, to treat HER2-positive breast cancer.

“We are not the first to report the anticancer effects of metformin,” Yang says. “However, among the recent advances of metformin as an anticancer agent, we have original findings showing that metformin selectively inhibits tumor-initiating cells and mammary stem cells in mammary tissues from the risk window of mammary tumor development in clinically relevant animal models.”

The research team has also “continued to explore the potential of repurposing buformin, an orphan drug of the metformin family, no longer being actively used for diabetes treatment, but instead as a cancer preventative."

In a paper published in the Journal of Experimental & Clinical Cancer Research on Feb.13, Yang and his team compared the preventative potential of type 2 diabetes drugs metformin and buformin with cancer treatments like lapatnib, first approved by the FDA in 2007 for the treatment of advanced HER2-positive breast cancer.

“Our study suggests that short-term, low-dose lapatinib exposure during the premalignant phase of breast cancer development is a promising strategy to prevent the development of erbB-2-overexpressing mammary tumors,” Yang states.

According to the paper, “Although buformin was shown to reduce mammary tumor burden in carcinogen models, the anticancer effects of buformin on different breast cancer subtypes and the underlying mechanisms remain unclear. Therefore, we aimed to investigate the effects of buformin on erbB-2-overexpressing breast cancer with in-vitro and in-vivo models.”

Buformin “was withdrawn from the market as a type 2 diabetes drug due to increased risk of a serious side effect called lactic acidosis, but it is still used in some European countries today,” Yang says. Lactic acidosis, a consequence of lactate buildup from mitochondrial complex I inhibition, was a fatal side-effect associated with phenformin and buformin treatment in about half of the patients who developed this complication, according to researchers.

“Unfortunately, the risk of harmful side effects outweighed the clinical benefits, and clinical trials investigating the anticancer effects of these drugs were terminated,” he says. “In the past decade, renewed interest in biguanide agents as cancer preventative and treatment options have emerged due to the association of metformin with cancer prevention in type 2 diabetes patients.”

In light of recent reports “indicating the anticancer benefits of metformin, buformin is currently being tested to explore the anticancer potential of biguanide drugs,” Yang says. “Recent reports suggest that buformin may be more potent than metformin. More relevant studies may lead to the development of novel biguanide drugs for anticancer purposes.”

The term biguanide refers to a group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver, improving the body’s sensitivity toward insulin and reducing the amount of sugar absorbed by the intestines.

Yang also studied the impact of dietary factors on breast cancer subtypes. Research published in the International Journal of Oncology in September 2016 indicated that genistein, a major component of soy found in some studies to reduce breast cancer risk, inhibits the activity of CIP2A, a well-known oncogene. Yang theorizes that this presents an opportunity to develop an anticancer drug that mimics genistein’s natural molecular activity. However, despite genistein functioning as a multi-targeting antitumor agent, the mechanisms of genistein-mediated tumor inhibition remain unclear.

Yang has also explored the impact of alcohol exposure on TNBC, a subtype of breast cancer characteristically associated with poor prognosis.

Using cell line models “to examine the effects of alcohol on the migration and invasion of TNBC cells in vitro, our results suggest a link between alcohol exposure and TNBC cell invasiveness,” according to researchers. “Our data would suggest that abstaining from alcohol could help prevent/treat TNBC, which need to be further validated in clinical settings.”

Breast cancer is one of the most common cancers threatening women and its global incidence is still increasing, according to the National Institutes of Health. It is the second leading cause of cancer-related deaths in women, which accounts for approximately 15 percent of all female cancer-related deaths in the United States.