UC Irvine-led study shows common diabetes drug may be effective against bladder cancer

Higher concentration in urine found to be more therapeutic than in the bloodstream

February 26, 2016

The accumulation of a high concentration of the common diabetes drug metformin in urine shows promise in inhibiting the growth of bladder cancer tumors, according to findings published today in Molecular Cancer Therapeutics, a journal of the American Association of Cancer Research.

Led by Xiaolin Zi, PhD, a professor of urology in the University of California, Irvine School of Medicine, and colleagues from UC Irvine, New York University and McGill University, the study examined whether metformin treatment in mouse models of bladder cancer demonstrated anti-tumor activity.

“Bladder cancer is a major public health challenge, as the treatment cost per patient from diagnosis to death is among the highest of all cancers in the U.S.,” said Zi. “Developing a safe, convenient, low-cost drug that can be taken orally for the prevention and treatment of disease recurrence is a clear priority in urologic oncology.”

Zi’s group concluded that the accumulated concentration of orally administered metformin in urine is about 240 fold higher than in the bloodstream. This elevated concentration exposes bladder cancer tumors to a therapeutically effective dosage of metformin not attainable for other types of cancer, which are exposed to metformin via the bloodstream. They found that the high concentration accumulated in the mouse bladder was sufficient to interfere with the mTOR signaling pathway, which is associated with maintaining bladder cancer cell metabolism and function.

“We believe our findings justify carefully designed clinical trials to determine whether high concentration oral doses of metformin in early bladder cancer might be effective, despite disappointing clinical trials for other cancers in which the drug exposure levels in the bloodstream were far lower,” Zi said.

Superficial bladder cancer is the most common cancer of the bladder and urinary tract. Despite current treatments such as transurethral resection and intravesicular BCG or mitomycin C, it is associated with high risk of recurrence and/or progression to invasive and metastatic disease. Many of the current chemotherapeutic regimens carry significant side effects and toxicities. 

Zi said there has been a paucity of new medications for the treatment of superficial bladder cancer. Valrubicin in 1998 was the last intravesical agent to be approved by the FDA.  This research presents the possibility of using a safe, well-tolerated, oral medication to decrease bladder tumor recurrence and progression with minimal cost (generic, under 30 cents/pill). He said the next step is a collaboration with Dr. Edward Uchio, the director of urological oncology and clinical research for UC Irvine Health and associate professor of urology in the UC Irvine School of Medicine, on planning a clinical trial of metformin for superficial bladder cancer patients.

About 74,000 new cases of bladder cancer are reported annually in the U.S.  The American Cancer Society estimates that 16,000 Americans will die from the disease this year.

The study, “High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin,” was conducted by Zi and colleagues Zhongbo Liu, Noriko N. Yokoyama, Chris A. Blair, Xuesen Li, Daina Avizonis, Xue-Ru Wu, Edward Uchio, Ramy Youssef, Michael McClelland, and Michael Pollak.

It was supported in part by National Institutes of Health awards 5R01CA122558-05 and 1R21CA152804-01A1 and an award from the Terry Fox Cancer Research Institute.

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