Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany.
Elife. 2024 Sep 30;13:RP91941. doi: 10.7554/eLife.91941.
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy.
High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy.
Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy.
Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects.
This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).
化疗引起的周围神经病变（CIPN）是常用抗癌药物的一种严重的治疗限制的副作用。先前的研究表明，脂质可能在 CIPN 中起作用。因此，本研究旨在确定紫杉醇给药后被调节的特定类型的脂质，这些脂质可能与治疗后神经病变的发生有关。
应用高分辨率质谱脂质组学定量分析 31 例乳腺癌患者在紫杉醇治疗前后的血液中 d=255 种不同的脂质介质。应用多种有监督的统计和机器学习方法来识别在紫杉醇治疗过程中被调节的脂质，或在有或没有治疗后神经病变的患者中存在差异的脂质。
确定了 27 种脂质，这些脂质携带的信息可用于训练机器学习算法，以识别新病例中血液样本是在紫杉醇治疗前还是治疗后采集的，中位数平衡准确率高达 90%。其中一个最高的命中是鞘氨醇-1-磷酸（SA1P），它通过瞬时受体电位香草素 1（TRPV1）通道和鞘氨醇-1-磷酸受体诱导感觉神经元中的钙瞬变。鞘氨醇-1-磷酸（SA1P）在有或没有神经病变的患者之间的血液浓度也不同。
目前的研究结果表明，鞘氨醇-1-磷酸在紫杉醇诱导的与神经副作用相关的生物学变化中起作用。所鉴定的 SA1P 通过其受体，可能为紫杉醇联合治疗提供一个潜在的药物靶点，以减少其主要的和治疗限制的副作用之一。
本工作得到德国研究基金会（DFG，SFB1039 A09 和 Z01 资助）和弗朗霍夫基金会项目：神经病理性疼痛以及弗朗霍夫免疫介导疾病卓越集群（CIMD）的支持。这项工作还得到了由弗朗霍夫学会和黑森州科学和艺术部资助的创新治疗学卓越中心（TheraNova）的支持。Jörn Lötsch 得到了德国研究基金会（DFG LO 612/16-1）的支持。
