VAI study finds new biomarker could identify tumors sensitive to diabetes drug

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Dr. Russell Jones Courtesy Van Andel Institute

A study led by Van Andel Institute’s Dr. Russell Jones recently identified a new biomarker that could help scientists pinpoint which cancers are vulnerable to treatment with biguanides.

Biguanides are a common class of medications used to control blood sugar in Type 2 diabetes. They, particularly a medication called metformin, have long been of interest to cancer researchers because of their ability to target cellular metabolism, which fuels the growth and spread of cancer cells.

To date, the success of biguanides as potential cancer therapeutics has been mixed, largely because of difficulty in getting enough of the agent into cancer cells to be effective and the lack of a way to determine which cancers will respond to treatment.

“Cancers vary widely in how they react to different therapies — what works for one cancer type may not work for another — but regardless, they are all reliant on metabolism for energy production,” Jones said.

“Our results establish two important things: First, they give us a way to objectively determine which types of cancer are sensitive to biguanide treatment and, second, they illuminate how and why some patients may respond better to biguanides than other patients.”

The findings, published in Cell Reports Medicine, identify a microRNA regulated by the gene MYC as a biomarker for cancers sensitized to biguanide treatment.

MYC is a well-known cancer-related gene whose activity is increased in as many as 70% of lymphomas. MYC works partly by turning down the activity of other genes that suppress tumor growth while heightening metabolic activity in cancer cells, a combination that allows the cells to flourish.

There is a trade-off, however. While MYC helps fuel cancer cells’ appetites, it also turns off cells’ ability to respond to a stressful biological environment, limiting flexibility in their metabolism.

Treatment with biguanides cuts off this energy supply, causing stress to cancer cells and leading them to die. In Type 2 diabetes, biguanides are used to lower blood sugar, but the increased stress kills certain cancer cells like lymphomas with high MYC expression.

“Biguanides have great potential as cancer treatments, particularly for blood cancers,” Jones said. “Biomarkers such as what we have found here are vital tools for determining which cancers will respond to biguanides and which will not, which is important for patient care, as well as designing more effective clinical trials.”

Jones and his colleagues also characterized an experimental biguanide called IM156, which is more potent than existing biguanides. IM156 was developed by ImmunoMet Therapeutics, a clinical-stage biotechnology company that develops anti-tumor and anti-fibrotic therapies.

The study’s other authors include Said Izreig, Alexandra Gariepy, Ariel O. Donayo, Gaëlle Bridon, Daina Avizonis, Ph.D., and Thomas F. Duchaine, Ph.D., of Goodman Cancer Research Centre, McGill University; Irem Kaymak, Ph.D., Lisa M. DeCamp, Susan M. Kitchen-Goosen, Ryan D. Sheldon, Ph.D., and Kelsey S. Williams, Ph.D., of Van Andel Institute; Hannah R. Bridges, Ph.D., of University of Cambridge; Rob Laister, Ph.D., and Mark D. Minden, Ph.D., MD, FRCPC, of Princess Margaret Cancer Centre, University of Toronto; Nathalie A. Johnson, Ph.D., and Michael N. Pollak, MD, of Lady Davis Institute, McGill University; and Marc S. Rudoltz, MD, and Sanghee Yoo, Ph.D., of ImmunoMet Therapeutics.

Goodman Cancer Research Centre Metabolomics Core Facility and the Metabolomics and Bioenergetics Core at Van Andel Institute contributed to this work.

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