Inflammatory oxylipins and aromatase inhibitor toxicity in breast cancer

项目总结 使用芳香酶抑制剂(AI)治疗，显著降低循环雌激素浓度， 5年至10年可将10年乳腺癌死亡率降低约40%。然而，人工智能相关的肌肉骨骼 症状(AIMSS)影响多达一半的接受治疗的患者，导致对治疗的依从性和依从性较差，以及 会增加乳腺癌的复发和死亡率。几乎没有确定有效的管理选择。 AIMSS的病因仍然知之甚少，尽管人们认为它至少部分是由雌激素引起的 剥夺和发炎。 氧合脂质介体来源于omega-3和omega-6脂肪酸，是支持或反对的。 炎症，并与炎症相关的疼痛有牵连。此外，已知雌激素可 影响脂肪酸的新陈代谢。AI治疗的非靶向脂质组学研究的初步数据 患者确定了多不饱和脂肪酸(PUFA)在有和没有发生的患者中的数量差异 开发AIMSS。基于这些数据，中心假设是氧脂素，它是多不饱和脂肪酸的代谢物，可能 在AIMSS的发展中发挥作用，通过雌激素剥夺诱导氧脂向亲-脂肪转化。 炎症性omega-6脂肪酸衍生代谢物。此外，遗传易感性改变的活动 参与氧脂代谢的关键酶可能进一步影响个体发生AIMSS的风险 病人。这一假设将通过分析先前进行的临床试验的样本和数据来检验。 开始人工智能治疗的女性。血浆样本、生殖系DNA和患者报告的结果将用于 研究的具体目的如下：(1)探讨雌激素剥夺联合人工智能治疗对大鼠心脏功能的影响。 氧脂分布，(2)检查氧脂变化与人工智能治疗和发展之间的关系 AIMSS，以及(3)评估与氧脂代谢相关的遗传改变与 人工智能治疗患者体内氧脂代谢产物的模式。 通过这一机制研究，我们将了解人工智能治疗和雌激素剥夺对炎性反应的影响 脂质介体，即氧脂及其在AIMSS发生中的作用，并可确定预测因素 AIMSS的开发。这些对AIMSS病因学的重要见解可能导致机制- 基于旨在预防或治疗这种治疗的干预措施--紧急毒性。阻碍发展 AIMSS可以改善乳腺癌幸存者的生活质量，并可以增加对AI治疗的依从性 并降低乳腺癌复发和死亡率。

PROJECT SUMMARY Treatment with an aromatase inhibitor (AI), which significantly decreases circulating estrogen concentrations, for 5-10 years reduces 10 year breast cancer mortality by about 40%. However, AI-associated musculoskeletal symptoms (AIMSS) affect up to half of treated patients, cause poor adherence and compliance with therapy, and can increase breast cancer recurrence and mortality. Few effective management options have been identified. The etiology of AIMSS remains poorly understood, although it is thought to be due, at least in part, to estrogen deprivation and inflammation. The oxylipin lipid mediators, which are derived from omega-3 and omega-6 fatty acids, are pro- or anti- inflammatory, and have been implicated in inflammation-related pain. In addition, estrogens are known to influence the metabolism of fatty acids. Preliminary data from an untargeted lipidomics study of AI-treated patients identified quantitative differences in polyunsaturated fatty acids (PUFA) in patients who did and did not develop AIMSS. Based on these data, the central hypothesis is oxylipins, which are metabolites of PUFA, may play a role in the development of AIMSS, through an estrogen deprivation-induced shift in oxylipins to pro- inflammatory omega-6 fatty acid-derived metabolites. In addition, genetic predisposition to altered activity of the key enzymes involved in oxylipin metabolism could further influence the risk of developing AIMSS in individual patients. This hypothesis will be tested by analyzing samples and data from a previously conducted clinical trial of women starting AI therapy. Plasma samples, germline DNA, and patient-reported outcomes will be used to investigate the following Specific Aims: (1) to investigate the effect of estrogen deprivation with AI therapy on oxylipin profiles, (2) to examine associations between change in oxylipins with AI therapy and development of AIMSS, and (3) to evaluate associations between genetic alterations related to metabolism of oxylipins and patterns of oxylipin metabolites in AI-treated patients. Through this mechanistic study we will learn the impact of AI therapy and estrogen deprivation on inflammatory lipid mediators, namely oxylipins, and their role in the development of AIMSS, and may identify predictors of development of AIMSS. These important insights into the etiology of AIMSS can potentially lead to mechanism- based interventions designed to prevent or treat this treatment-emergent toxicity. Preventing the development of AIMSS can improve quality of life for breast cancer survivors, and could increase compliance with AI therapy and reduce breast cancer recurrence and mortality.