Giving an Old Drug New Potential

Balaraman Kalyanaraman, PhD
The results of Dr. Kalyanaraman's work to modify a well-established diabetes drug (metformin) for use in pancreatic cancer were published in the August 2016 issue of Cancer Research.

In the typical progression of biomedical science, basic research into the fundamental principles of biology and other fields leads to potential treatments that must be tested in clinical trials for safety and effectiveness. Once shown to be effective, these therapies enter the marketplace and then are further studied by public and population health researchers. While this process may be the tidy theoretical model, sometimes ideas flow against the tide.

"Epidemiology studies have shown that diabetic patients taking metformin have less incidence of pancreatic cancer," says Balaraman Kalyanaraman, PhD, chair and professor of biophysics and the Harry R. & Angeline E. Quadracci Professor in Parkinson's Research at the Medical College of Wisconsin (MCW). Findings by epidemiologists, who focus on patterns of health and disease in populations, suggested that there may be a way to modify and repurpose metformin, which regularly is prescribed to reduce glucose production in the liver and help control blood sugar levels in patients with type 2 diabetes.

Metformin has had a strong safety record in treating type 2 diabetes for more than 50 years, and Dr. Kalyanaraman was eager to apply what statistical analysis had uncovered in large populations to new studies in cellular and rodent models of pancreatic cancer.

The Kalyanaraman lab hypothesized that off-the-shelf metformin needed some modifications to unleash its potential as a future therapy for pancreatic cancer. The researchers then developed new versions that would be more positively charged, so that the compounds would accumulate more in the negatively charged mitochondria – thus improving the drug's ability to decrease the proliferation and growth of cancer cells. The results were published in the August 2016 issue of Cancer Research.

MCW research scientist Gang Cheng, PhD, working under the supervision of Dr. Kalyanaraman, is the first author of the manuscript.

Gang Cheng, PhD
Gang Cheng, PhD

The work described in the article received financial support from the MCW Cancer Center, the National Institutes of Health's National Cancer Institute, Aix-Marseille University in Provence, France and the French National Center for Scientific Research. The MCW Cancer Center pilot grant was instrumental in obtaining the reported data.

Also crucial were his scientific collaborations, both at MCW and across the world. Michael Dwinell, PhD, MCW professor of microbiology and immunology and principal investigator, contributed expertise on reducing tumor growth and metastasis in pancreatic cancer, while Bryon Johnson, PhD, MCW professor of pediatrics, added expertise in cancer immunology. Former MCW postdoctoral fellows Micaël Hardy, PhD [and his colleague Olivier Ouari, PhD], from Aix-Marseille University, and Marcos Lopez, PhD, from the Cardiovascular Foundation of Colombia, assisted with synthetic chemistry. Other MCW contributors included Christy Barrios, PhD; Kathleen Boyle, PhD; Donna McAllister; James Weber; and Jacek Zielonka, PhD.

The investigators now plan to move forward by seeking a patent and opportunities for clinical trials. Their evidence also suggests possible uses for the new compound beyond pancreatic cancer.

Dr. Kalyanaraman in the lab

Equipment in Dr. Kalyanaraman's lab

"The more we learn about mechanisms of action, the clearer it becomes that we can use this approach on other cancers," Dr. Kalyanaraman adds.

– Greg Calhoun

MCW Magazine: Discovery story

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