Deoxysphingolipids as intermediates of taxane-induced peripheral neuropathy (RPA Pilot / Seed Projects)

Taxane-induced peripheral neuropathy (TIPN) is a major side effect of chemotherapy that impacts approximately 50% of patients. Symptoms of TIPN include pain, numbness and tingling in the feet and hands, and motor neuropathies leading to muscle weakness and difficulty with fine motor movements such as the manipulation of small objects. TIPN causes breast cancer patients to reduce dose (9.4%) or terminate taxane treatment altogether (28.4%). TIPN not only undermines the success of taxane therapy, but also can impact quality of life for months, and in some cases even years after the completion or termination of taxane therapy.The neurotoxic effect of taxanes are largely a result of distal axonal degeneration, yet the molecular mechanism are poorly understood. The overall objective of this project is to provide a direction to develop treatment strategy based on the identified neurotoxic pathways downstream from deoxySL. Such approaches will be valuable in treatment of TIPN and other types of neuropathies, such as HSAN1 and diabetic neuropathy, where deoxySL were identified as intermediates. We will test the hypothesis that the mechanism of deoxySL neurotoxicity includes damage to neurites, leading to cytoskeletal deregulation in neurons. Data from our recent publications support our novel hypothesis that taxane neurotoxicity is indirect, mediated by upregulation of the first enzyme of sphingolipid biosynthesis, SPT, which then generates neurotoxic levels of deoxySL leading to neuropathy.