Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan.
Division of Medical Safety Science, National Institute of Health Sciences, Kawasaki, Japan.
Cancer Sci. 2019 Oct;110(10):3267-3274. doi: 10.1111/cas.14178. Epub 2019 Sep 19.
Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ-induced peripheral neuropathy (BiPN), a frequent side-effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty-nine serum samples were collected from patients with MM prior to receiving BTZ plus low-dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients' sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet-activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.
虽然蛋白酶体抑制剂硼替佐米（BTZ）在多发性骨髓瘤（MM）中显示出优异的疗效，但仍有一部分患者对此药物反应不佳或无反应。此外，BTZ 诱导的周围神经病变（BiPN）是这种治疗的常见副作用，限制了其在某些患者中的使用。本研究旨在探讨血清脂质生物标志物候选物，以预测对 BTZ 的反应和 BiPN 的严重程度。在接受 BTZ 联合低剂量地塞米松治疗之前，从 59 例 MM 患者中采集了 59 份血清样本。通过全面的脂质组学研究测量了血清磷脂、鞘脂、中性脂质和多不饱和脂肪酸及其氧化产物的水平。总体而言，在患者血清中鉴定出 385 种脂质代谢物；几种甘油磷脂、鞘脂和胆固醇酯水平降低与治疗反应不佳相关。与血小板激活因子生物合成和胆固醇代谢相关的代谢物似乎特别相关。此外，在 BiPN 分级从 G0 到 G3 的患者中，几种溶血磷脂酰胆碱、磷脂酰胆碱、神经酰胺、中性脂质和氧化脂肪酸显著增加或减少。在这些化合物中，据报道可诱导髓鞘破坏和刺激炎症反应的介质较为突出。尽管需要进一步研究来验证这些生物标志物候选物，但我们的结果有助于开发预测 MM 患者对 BTZ 治疗反应或随后发生严重 BiPN 的生物标志物。
