MS Drug Could Reduce Adverse Events Associated With Cancer Treatment

In a recent study published in the Journal of Experimental Medicine, researchers found that fingolimod (sold as Gilenya), an FDA-approved orally administered drug to treat multiple sclerosis, could reduce painful side effects of multiple myeloma treatments.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and painful side effect of many anticancer drugs that can persist for years and reduce the quality of life for cancer survivors. Bortezomib (sold as Velcade), used to treat multiple myeloma and mantle cell lymphoma, causes CIPN in over 40% of patients; however, the reason behind this had previously been unidentified.

Researchers from the Saint Louis University School of Medicine have discovered that bortezomib causes the dysregulation of sphingolipid metabolism in the spinal cord and increases the levels of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate. Higher levels of these molecules can activate a cell surface receptor protein called S1PR1.

The activation S1PR1 happens on the surface of specialized nervous system support cells called astrocytes, resulting in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

In a rat model, rats that were treated with bortezomib showed higher accumulations of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate at the time that they started to show signs of neuropathic pain. By blocking the production of these molecules with the fingolimod inhibitor, researchers prevented the animals from developing CIPN and were even able to reverse the effects.

Notably, fingolimod did not inhibit bortezomib’s ability to kill myeloma cells. In fact, fingolimod has previously been reported to inhibit tumor growth and enhance the effects of bortezomib in vitro and in tumor-bearing animals in other studies.

“Our studies provide a compelling case for the consideration of repurposing [fingolimod] as an adjuvant to bortezomib for the prevention and treatment of chemotherapy-related neurotoxicity to address an immense unmet medical need,” concluded the study. “As [fingolimod] also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.”

Reference

Stockstill K, Doyle T, Yan X, et al. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med. 2018;215(5):1301-1313. doi: 10.1084/jem.20170584.