UW-Madison School of Medicine and Public Health: UW scientists use diabetes drug to stress out prostate cancer

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Susan Lampert Smith
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MADISON, Wis. — The potential benefit of combining the commonly prescribed diabetes drug metformin with standard advanced prostate cancer treatment is the subject of a $1.1 million grant awarded to University of Wisconsin Carbone Cancer Center (UWCCC) researchers.

The three-year Department of Defense grant will fund prostate cancer research in the labs of both David Jarrard, professor of urology and associate director of translational research at UWCCC, and Vincent Cryns, professor of medicine and chief of the division of endocrinology, diabetes and metabolism. The proposed research will investigate if prostate cancer patients who are also taking metformin for diabetes management have better outcomes, and will seek to identify how the diabetes drug works at the molecular level in advanced prostate cancer cells.

Most prostate cancers are dependent on androgens, or male sex hormones, to continue growing. A typical treatment protocol for advanced prostate cancer is to put the patient on androgen deprivation therapy (ADT), to, as its name suggests, deprive the cancer cells of this needed growth signal.

“Many tumor cells die from ADT, but some just sit there in a state known as senescence. They do not grow and divide, but they do not die,” Jarrard said. “Senescent cells are generally not good over time because they secrete a lot of pro-growth, pro-inflammation, pro-oncogenic substances that can lead to recurrence.”

But senescent cells have a weakness: because they are metabolically active, they accumulate unfinished or damaged proteins, leading to a state of “proteotoxic” stress. Senescent cells activate an adaptive stress response that allows them to survive. This stress-response pathway is a key biological difference between senescent tumor cells and normal cells, and one that can be exploited for treatment purposes.

“Dr. Jarrard has shown that metformin kills senescent cells. My lab is going to look at the idea that metformin is killing senescent cells by shutting down this key survival pathway,” Cryns said. “Understanding metformin’s mechanism of action will allow us to maximize its therapeutic benefit.”

Cryns’s research group will work with tissue culture models of prostate cancer to understand how metformin specifically targets senescent prostate cancer cells. Jarrard and his group will generate pre-clinical data from mouse models to determine which treatment order and combinations of metformin and ADT have the greatest benefits.

The grant also includes co-investigator Kyle Richards, assistant professor of urology, who will access the wealth of data from the Department of Veterans Affairs. He will look at prostate cancer patients who have been treated with ADT and compare their outcomes with diabetic prostate cancer patients who have been treated with ADT and metformin.