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New Research Finds Clues to Reducing Bortezomib-Linked Neuropathy

By: Celeste L. Dixon
Posted: Friday, June 8, 2018

Painful chemotherapy-induced peripheral neuropathy is an adverse effect of many chemotherapeutic drugs, including bortezomib. More than 40% of patients taking bortezomib for multiple myeloma and mantle cell lymphoma develop chemotherapy-induced peripheral neuropathy, but newly discovered mechanisms that may explain why—and how they can potentially be blocked—have been described in the Journal of Experimental Medicine. The research team was led by Daniela Salvemini, PhD, of Saint Louis University School of Medicine.

One blocking agent is fingolimod, already approved by the U.S. Food and Drug Administration (FDA) to treat multiple sclerosis. In separate research, it has also shown promise in inhibiting tumor growth and in enhancing bortezomib’s positive effects.

Using rodents, Dr. Salvemini and colleagues discovered that bortezomib quickens the production of sphingolipids, fat molecules previously linked to neuropathic pain. The spinal cords of the bortezomib-dosed animals developed two sphingolipid metabolites, which activated a cell surface receptor protein called S1PR1. When S1PR1 emerged on the surface of astrocytes, neuroinflammation and over-release of the neurotransmitter glutamate resulted, leading to chemotherapy-induced peripheral neuropathy.

Fingolimid, among other drugs, was found to inhibit S1PR1 production and thus prevent the animals from developing chemotherapy-induced peripheral neuropathy in response to bortezomib.

“Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways,” the investigators stated. According to a report in Myeloma Research News, Dr. Salvemini also thinks their findings can be “rapidly” translated to the clinic, “because fingolimod shows promising anticancer potential and is already FDA approved.”

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