Metabolic Phenotypes of Doxorubicin-induced Cardiotoxicity in Breast Cancer

项目总结/摘要 多柔比星（DOX）是一种高效的化疗剂，其通常与化疗药物联合使用。 精准医学用于治疗各种癌症，包括32%的乳腺癌（BC）病例。虽然 治疗大大增加了长期癌症幸存者的数量，也增加了癌症患者的数量。 发生DOX诱导的心脏毒性（DIC）的患者。目前，还没有经过验证的生物标志物可以 预测DIC的早期发展。心肌细胞释放的心肌肌钙蛋白已被用于非临床 作为心肌损伤标志物的研究;然而，它的特异性较低， 心脏毒性有限。因此，迫切需要新的DIC生物标志物来识别处于 增加的风险，使心脏毒性的早期检测之前，它会导致永久性心脏损伤。 最近的研究已经确定了在DIC期间心脏中改变的新途径， 心脏毒性的早期生物标志物的鉴定。DOX被线粒体复合物I还原以形成一个线粒体复合物。 半醌自由基，导致多种细胞分子的氧化，包括脂质过氧化 和氧化磷脂。这些代谢改变可用于开发DIC生物标志物。 代谢组学识别由于毒性和疾病引起的分子途径扰动，非常适合于 识别DIC的早期迹象。此前，我们的研究团队报告了心脏中的早期代谢物变化， 和血浆中，并确定了在最低水平下Krebs循环相关代谢物的改变水平。 在肌钙蛋白释放到血液中和心脏病变出现之前，DOX的累积剂量。我们的目标是 鉴定血液中与心脏功能障碍相关的心脏毒性的早期代谢物标志物。在 与PI的2名COBRE导师合作，我们的实验室是正在进行的DOX治疗BC临床研究的一部分 患者我们先前已经确定了左心室收缩功能异常下降的患者队列， 射血分数和维持正常心功能的患者。我们将进行非靶向代谢组学 在DIC的大鼠BC模型中分析以检查早期血浆代谢物标志物，可视化它们在DIC中的空间位置， 心脏组织，然后确定BC患者中代谢产物谱模式的变化，以检验假设 DOX产生一种由氧化脂质和代谢物组成的"代谢型"， BC患者中DIC的指标。我们的具体目标是：1）确定DOX对心功能的影响 以及在BC的MATBIII大鼠模型中血浆和心脏的代谢概况;以及2）确定在BC的MATBIII大鼠模型中血浆和心脏的动态代谢概况。 与DIC相关的BC患者血浆代谢谱的变化。拟议研究 通过鉴定早期蒽环类药物心脏毒性的血浆代谢标志物， 等离子体此外，心脏组织中代谢改变的信息将促进我们的生物学和机制 通过BC患者中紊乱的代谢途径了解DIC。

PROJECT SUMMARY/ABSTRACT Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with precision medicine to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although the treatment has greatly increased the number of long-term cancer survivors, it has also increased the number of patients experiencing DOX-induced cardiotoxicity (DIC). Currently, there are no validated biomarkers that can predict the early development of DIC. Cardiac troponin released by cardiomyocytes has been used in non-clinical studies as a marker of myocardial injury; however, it has a low specificity, and the predictive value on cardiotoxicity is limited. Therefore, novel biomarkers of DIC are urgently needed to identify patients who are at an increased risk, allowing early detection of the cardiotoxicity before it causes permanent cardiac damage. Recent studies have identified new pathways that are altered in the heart during DIC, providing opportunities for the identification of early biomarkers of cardiac toxicity. DOX is reduced by mitochondrial complex I to form a semiquinone free radical, resulting in the oxidation of a variety of cellular molecules, including lipid peroxidation and oxidized phospholipids. These metabolic alterations can be leveraged to develop DIC biomarkers. Metabolomics identifies perturbations in molecular pathways due to toxicity an‐d disease and is ideally suited for identifying early indications of DIC. Previously, our research team reported early metabolite changes in the heart and plasma of DOX-treated mice and identified altered levels of Krebs cycle related metabolites at the lowest cumulative dose of DOX, before troponins are released into the blood and cardiac lesions appear. Our goal is to identify early metabolite markers of cardiotoxicity in blood that are associated with cardiac dysfunction. In collaboration with the PI's 2 COBRE mentors, our lab is part of an ongoing clinical study of DOX-treated BC patients. We have previously identified cohorts of patients who developed an abnormal decline in left ventricular ejection fraction and patients who maintained normal cardiac function. We will perform untargeted metabolomics profiling in a rat BC model of DIC to examine early plasma metabolite markers, visualize their spatial location in the heart tissue, and then identify changes in patterns of metabolite profiles in BC patients to test the hypothesis that DOX produces a “metabotype” consisting of oxidized lipids and metabolites that can be used as early indicators of DIC in BC patients. Our Specific Aims are: 1) Determine the effects of DOX on cardiac function and metabolic profiles of the plasma and heart in the MATBIII rat model of BC; and 2) Determine the dynamic changes in plasma metabolomic profiles of BC patients that are associated with DIC. The proposed research will have a significant impact by identifying plasma metabolic markers of early anthracycline cardiotoxicity in plasma. Moreover, information on metabolic alterations in heart tissue will advance our biologic and mechanistic understanding of DIC through metabolic pathways that are perturbed in patients with BC.