33: Sphinganin- and Sphingosing-1-Phosphat Receptors in Chemotherapy Induced Peripheral Neuropathy

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Pharmacological interventions

Background and Aims: Chemotherapy induced peripheral neuropathy (CIPN) is a common dose limiting toxicity of many first line anticancer drugs, especially occurring under therapy with platinum compounds, taxanes, vinca alkaloids, and bortezomib. Clinically, CIPN mainly occurs as a chronic sensory neuropathy with numbness, tingling, hypersensitivity as well as neuropathic pain which can persist for months to years after treatment and markedly impair quality of life. Even considerable efforts to develop a suitable therapy have not yet led to success and duloxetine is currently the only pharmacological option with moderate evidence, while no established preventive therapy exists. Here we show dysregulated sphingolipid and sphingosine 1 phosphate (S1P) receptor signaling as possible cause in CIPN, particularly in models of platinum induced peripheral neuropathy.

Methods: We investigated early molecular alterations using clinical plasma data from paclitaxel-treated cancer patients and an oxaliplatin-induced neuropathy mouse model to examine these changes in neuronal tissues. Patient data were analyzed using machine learning to identify molecular differences associated with the presence or absence of chemotherapy-induced peripheral neuropathy (CIPN). In the mouse model, CIPN was induced by intraperitoneal oxaliplatin injection, and after ten days - during the developmental phase of neuropathy - the spinal cord (SC) and dorsal root ganglia (DRG) were collected for further analysis. Gene expression of S1P receptors was conducted and compared with vehicle treated controls. Additionally, Calcium-Imaging was undertaken to examine the effect of sphingolipids on TRPV1 sensitization in wild type mice.

Results: Clinical data revealed elevated sphingolipids (including S1P an SA1P) in those Patients developing CIPN compared to non-neuropathic patients. We furthermore identified treatment associated alterations in the oxaliplatin model of S1P signaling components in both tissues DRG and SC whereas no differential regulation of distinct S1P receptor subtypes were observed. Neuronal Calcium-Imaging of primary sensory neurons of wild type mice revealed a sensitization of TRPV1 trough sphingolipids, which could be partially reversed by pharmacological attack through inhibition of S1P receptors.

Conclusions: Our data support the concept that disturbed Sphingolipid/S1P receptor signaling contributes to the early pathophysiology of chemotherapy induced peripheral neuropathy independent of the cytostatic drug class. Targeting specific S1P receptor subtypes may represent a promising strategy to prevent or ameliorate CIPN and thus enable optimal dosing of neurotoxic chemotherapeutics. Further work will be required to identify the relevance of individual S1P receptors using selective S1P modulators as potential analgesic or disease modifying interventions in CIPN.

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Stockstill, K., et al., Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med, 2018. 215(5): p. 1301-1313.
Loprinzi, C.L., et al., Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol, 2020. 38(28): p. 3325-3348.
Colvin, L.A., Chemotherapy-induced peripheral neuropathy: where are we now? Pain, 2019. 160 Suppl 1(Suppl 1): p. S1-S10.
Wang, W., et al., Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy. J Biol Chem, 2020. 295(4): p. 1143-1152.

Presenting Author: Max Bromberger
Submitting Author: Max Bromberger

Senior Author: Prof. Dr. Marco Sisignano

IASP 2026 Global Year theme of Neuropathic Pain: Yes