Metformin Plus Gene Inhibitor May Offer New Hope for Prostate Cancer

Low doses of the antidiabetic drug metformin, and a gene inhibitor known as BI2536 may be able to successfully halt the growth of late-stage prostate cancer tumors, according to a new study published in The Journal of Biological Chemistry. 

Researchers at Purdue University in West Lafayette, Indiana, found that these two agents may work synergistically to suppress castration-resistant prostate cancer based on their patient-derived xenograft studies.

Xiaoqi Liu, PhD, associate professor of biochemistry and cancer research, and colleagues found that metformin and BI2536 may be a promising way to treat late-stage prostate cancer with less toxicity.  They note that both agents are well tolerated, and may help those patients who are not cured by the current standards of care.  

BI2536 is the first Plk1 inhibitor to enter clinical trials.  This agent has been studied in phases I and II cancer trials and has been shown to be safe and well tolerated.  It is theorized that this agent may help stop the production of androgens, which are fueling the disease. Plk1 promotes androgen receptor signaling and acts as a negative regulator of tumor suppressor p53.

While the current standard of care includes ADT (androgen deprivation therapy), Liu said that new approaches for treating the most persistent forms of prostate cancer are urgently needed.  He noted that prostate cancer is the cause of the second biggest cancer killer in men in the United States.

ADT fails in many patients because castration treatment can inadvertently encourage the cancer to get tougher and heighten oxidative stress on the prostate gland.  Liu said this increases the expression of Plk1 and over-expression of Plk1 can trigger the synthesis of androgen.  He said prostate cancer cells eventually become smart enough to make androgen, which is why the cancer continues to grow.  It is hoped that these men with castration-resistant disease may benefit from this combination therapy.

Previous studies have demonstrated that metformin--which has been used for more than 40 years--is particularly active against prostate cancer tumors.  Increasing evidence suggests that metformin has several antitumor characteristic, and it has been shown to help lower the risk of developing castration-resistant prostate cancer. 

Researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both challenges.   The mice tumors were grown from the tumor of a late-stage prostate cancer patient.  Liu and his colleague's report that these agents combined help prevent androgen synthesis while not impacting healthy prostate cells.  Liu said the next step in the research is to test the combination in clinical trials.