Molecular Medicine Israel

Driver of Deadly Brain Cancer Discovered, Potential New Drug Target

Glioblastoma multiforme (GBM) is one of the most common, aggressive, and deadly brain cancers often difficult to remove surgically and developing resistance to radiation and chemotherapy. Now, a team of researchers at the University of Ottawa believes they have found a major driving force in tumor formation that could lead to the development of novel therapies to treat this intractable cancer.

“The fact that most patients with these brain tumors live only 16 months is just heartbreaking,” stated lead study author Arezu Jahani-Asl, Ph.D., who performed this work as a postdoctoral fellow at the University of Ottawa and is now an assistant professor at McGill University. “Right now there is no effective treatment, and that’s what drives me to study this disease.”

The research team studied human brain tumor stem cells taken from an array of GBM patients. Previously, it was believed that any cancer cell could reproduce to form a whole tumor; however, researchers have since learned that in brain cancer, only a few kinds of cells have this ability. If a single one of these brain tumor stem cells is left behind after surgery, it can create a whole new tumor. In this new study, the investigators found that a protein called the oncostatin M receptor (OSMR) was required for the formation of GBM tumors. More importantly, they discovered that blocking OSMR activity in these cells prevented them from forming tumors in mouse brains.

The findings from this study were published recently in Nature Neuroscience in an article entitled “Control of Glioblastoma Tumorigenesis by Feed-Forward Cytokine Signaling.”

“Being able to stop tumor formation entirely was a dramatic and stunning result,” explained co-senior study author Michael Rudnicki, Ph.D., professor in the departments of medicine and cellular and molecular medicine at the University of Ottawa. “It means that this protein is a key piece of the puzzle, and could be a possible target for future treatments.”

The scientists looked at 339 tumor samples from human GBM patients and found that the higher the OSMR expression, the faster the patient died. This was confirmed in mouse studies, where animals injected with human brain tumor stem cells with low OSMR expression lived 30% longer than those infected with tumor stem cells with normal OSMR expression.

Previous studies into GBM’s molecular mechanisms told researchers that an active form of the epidermal growth factor receptor called EGFRvIII drove tumor formation in GBM, but to date therapies targeting this receptor have not worked against brain cancer. The Ottawa team uncovered that EGFRvIII needs to bind with OSMR before it can send out any tumor-forming signals. This new understanding could pave the way for more effective treatments, not only for glioblastomas, but also for other cancers with highly amplified EGFR expression, like breast, lung, and cervical cancers.

“This study raises the exciting prospect of potential new targets for a lethal disease,” noted co-senior study author Azad Bonni, M.D., Ph.D., professor in the department of neuroscience at Washington University. “The next step is to find small molecules or antibodies that can shut down the protein OSMR or stop it from interacting with EGFR. But any human treatment targeting this protein is years away.”

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