Pharmaclogy of lipid mediators in Chemotherapy-induced neuropathy and neuroinflammation

• Applicant: Privatdozent Dr. Marco Sisignano
• Subject Area: Pharmacology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561966070

Chemotherapy-induced neuropathies and neuropathic pain represent a serious dose- and therapy-limiting side effect of numerous cytostatic drugs. Particularly concerning is the fact that first-line therapeutics such as paclitaxel and oxaliplatin, which are administered to millions of patients annually, cause neuropathies in up to 80% of those treated. Currently, however, no effective and approved treatment options for chemotherapy-induced neuropathic pain are available. Given the demographic trends and the expected global increase in cancer incidence in the coming years, a rise in the occurrence of chemotherapy-induced neuropathies and neuropathic pain is also anticipated. As part of this research project, we intend to analyze the role of sphingolipids, lysophospholipids, and oxylipins, along with their receptors and mechanisms of action in chemotherapy-induced neuropathy, based on our previous work and clinical investigations. Utilizing a "bedside-to-bench" approach, we aim to first closely examine those lipids that exhibited significant concentration changes in clinical samples and to understand the underlying mechanisms of their activity. This raises questions such as which receptors are responsible for sphingolipid-mediated TRPV1 sensitization and neuroinflammation, and which intracellular signaling pathways mediate the neuronal and neuroinflammatory effects of Sphingolipids, lysophospholipids, and oxylipins. Moreover, it remains unclear how treatment with cytostatics affects the neuronal lipidome and transcriptome, the secretion of neuroinflammatory mediators, and the recruitment of immune cells, as well as how intracellular changes induced by cytostatics impact the activity of neuronal mitochondria. Our preliminary work has demonstrated that the combination of omics approaches and machine learning in the context of chemotherapy-induced neuropathy leads to the generation of testable hypotheses. We seek to further develop and expand this approach within a systems biology and pharmacological framework by conducting various omics analyses and subsequently evaluating these using machine learning. Our central hypothesis is that sphingolipids, lysophospholipids, and oxylipins are significantly involved in the pathogenesis of chemotherapy-induced neuropathy and neuroinflammation through their modulation of receptors, ion channels, and intracellular signaling pathways. A deeper mechanistic understanding of these relationships is essential to identify new therapeutic options for chemotherapy-induced neuropathy and to improve patients' quality of life.

• DFG Programme: Research Grants