L-Serine Supplementation for Prevention of Taxane-Induced Peripheral Neuropathy

Taxanes (paclitaxel/ docetaxel) are microtubule-inhibiting chemotherapy drugs, widely used in the treatment of variety of cancers, e.g., breast, ovarian, lung, head and neck, and Kaposi’s sarcoma. A major dose-limiting side effect of taxane chemotherapy is peripheral neuropathy. Currently, the mechanism of taxane-induced neurotoxicity is poorly understood and there are no treatment options or prevention strategies available. To overcome this limitation, it is critical to understand the mechanism of taxaneinduced peripheral neuropathy and test novel treatment and/or prevention strategies based on this mechanism. In our recent study with breast cancer patients undergoing paclitaxel chemotherapy, we discovered that the incidence and severity of peripheral neuropathy was associated with increased plasma levels of deoxysphingolipids (deoxySL), a class of recently discovered neurotoxic sphingolipids. DeoxySL are produced when the first enzyme of the sphingolipid pathway, serine palmitoyltransferase (SPT), utilizes L-alanine, instead of its regular amino acid substrate, L-serine. The neurotoxicity of deoxySL was shown in vitro in neuronal cultures by others, by us, and in phase I clinical trials where the deoxySL, deoxysphinganine, was tested for its anticancer potential. The clinical trials were terminated because patients developed severe, and in some cases fatal, neurotoxicity. Importantly, our preliminary data showed elevated levels of deoxySL in the dorsal root ganglion of mice treated with docetaxel. Our preliminary data also showed that in taxane-treated cells, the increased levels of deoxySL are due to upregulation of the SPT enzyme. Accordingly, our central hypothesis is that the neurotoxic effect of taxanes is mediated by deoxySL due to SPT up regulation. Our current proposal will test the hypothesis that adding L-serine to taxane treatment will reduce the production of neurotoxic deoxySL and alleviate neuropathy symptoms. Sp. Aim 1 will investigate in in vitro culture models (immortalized Schwann cells, neuroblastoma cell lines and primary DRG neurons) whether adding L-serine to taxane treatment will decrease deoxySL levels, as well as establishing the kinetics involved by using stable isotope labeling combined with mass spectrometry. Sp. Aim 2 will test in a mouse model of taxane-induced peripheral neuropathy whether combining oral Lserine with systemic taxane treatment can be used as a prevention strategy for neuropathy. If proven, our hypothesis will provide bases for further mechanistic studies and in the development of prevention strategies of taxane-induced peripheral neuropathy based on reducing the generation of neurotoxic deoxySL by supplementing taxane treatment with oral L-serine.