A Multi-omics evaluation of Carfilzomib-related Cardiotoxicity

卡非佐米相关心脏毒性的多组学评估

• 批准号: 10652367
• 负责人: Yan Gong
• 金额: $ 37.59万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652367
• 关键词: Academic Medical Centers; Address; Adverse effects; Adverse event; Anthracycline; Biological Assay; Biological Markers; Cancer Center; Cancer Patient; Cardiotoxicity; Cardiovascular system; Characteristics; Clinical; Data; Development; Early Diagnosis; Evaluation; Florida; Functional disorder; Genes; Genetic; Genetic Markers; Goals; Heart failure; Hematology; Incidence; Intervention; Knowledge; Malignant Neoplasms; Mission; Morbidity - disease rate; Multiomic Data; Multiple Myeloma; National Heart, Lung, and Blood Institute; Oncology; Outcome; Pathway interactions; Patients; Performance; Pharmacogenomics; Population; Positioning Attribute; Prevention strategy; Prospective Studies; Proteasome Inhibitor; Proteomics; Reporting; Research; Research Personnel; Risk; Risk Factors; Risk Management; Sampling; Stratification; Symptoms; United States National Institutes of Health; Universities; Work; biobank; cancer therapy; clinical practice; clinical risk; clinical translation; electronic health record system; exome sequencing; genetic variant; high risk; improved; improved outcome; insight; metabolomics; mortality; multidisciplinary; multiple omics; patient population; predictive modeling; prevent; risk minimization; risk prediction; risk prediction model; risk stratification; tool

Cardiotoxicity related to cancer therapies is such a significant clinical problem that NCI and NHLBI have jointly issued PA-19-112 to stimulate applications with the intent to mitigate cardiovascular dysfunction while optimizing cancer outcomes. Cardiotoxicity, such as heart failure (HF), related to the proteasome inhibitor carfilzomib has been an increasingly recognized adverse event that contributes to the symptom burden and poor outcomes of multiple myeloma (MM) patients. Given the knowledge gap in the understanding of carfilzomib-related cardiotoxicity, a pharmacogenomic approach may identify pharmacogenomic/metabolomic biomarkers of such adverse effect and provide an opportunity to improve cardiovascular outcome of cancer patients in a personalized manner. Our long-term goal is to identify and institute preventive strategies for cancer patients at high risk for carfilzomib-related cardiotoxicity, prior to administration of this cardiotoxic treatment, in order to prevent or minimize such risk. Our central hypothesis is that characteristic biomarkers for carfilzomib-related cardiotoxicity can be discerned through interrogation of multi-omics data. Our preliminary results demonstrate the feasibility of such an approach and suggest that the metabolomic and proteomic profiles of carfilzomib-related HF are similar to those of HF in non-cancer patients. More importantly, our findings support the hypothesis that there are overlapping pathways in the development of cardiotoxicity induced by carfilzomib and anthracyclines. The overall objectives of this application are to identify and validate metabolomic and pharmacogenomic biomarkers for carfilzomib-related HF in MM patients using a multi-omics approach and existing whole exome sequencing (WES) data from the Oncology Research Information Exchange Network (ORIEN), and in large electronic health record (EHR) systems, namely the UK Biobank and biobank at Vanderbilt University (BioVU). We have assembled a multidisciplinary team to carry out the following three specific aims: 1). Identify and validate metabolomic biomarkers at baseline that differentiate MM patients who develop versus do not develop carfilzomib-related HF. 2). Identify and replicate germline genetic variants associated with carfilzomib-related HF among MM patients. 3). Build and validate a predictive model for carfilzomib-related HF among MM patients. The proposed work is expected to provide tools to enable stratification of MM patients for cardiotoxicity risk based on pharmacogenomic and metabolomic biomarkers and provide the basis for clinical translation of these biomarkers. In addition, this work will also provide important insight as to what extent the genetic variants associated with anthracycline-related cardiotoxicities are also associated with carfilzomib-related HF. Ultimately, our research will potentially lead to a paradigm shift in current clinical practice to better prevent cardiotoxicity, and improve outcomes in the MM patient population.

与癌症治疗相关的药物毒性是如此重要的临床问题，NCI和NHLBI已经联合研究了 发布PA-19-112，以刺激旨在减轻心血管功能障碍的应用，同时优化 癌症结果。与蛋白酶体抑制剂卡非佐米相关的药物毒性，如心力衰竭（HF）， 已成为一种日益被认识到的不良事件，会导致症状负担和不良结局 多发性骨髓瘤（MM）患者。鉴于对卡非佐米相关药物的理解存在知识差距， 心脏毒性，药物基因组学方法可以鉴定这种毒性的药物基因组学/代谢组学生物标志物。 并提供改善癌症患者心血管结局的机会， 个性化的方式。我们的长期目标是为癌症患者确定和制定预防策略， 卡非佐米相关心脏毒性的高风险，在给予这种心脏毒性治疗之前， 避免或减少这种风险。我们的中心假设是卡非佐米相关的特征性生物标志物 可以通过询问多组学数据来辨别心脏毒性。我们的初步结果表明 这种方法的可行性，并表明卡非佐米相关的代谢组学和蛋白质组学特征 HF与非癌症患者的HF相似。更重要的是，我们的发现支持了这样一个假设， 在卡非佐米和蒽环类药物诱导的心脏毒性的发展中存在重叠的途径。 本申请的总体目标是识别和验证代谢组学和药物基因组学 使用多组学方法和现有全外显子组在MM患者中检测卡非佐米相关HF的生物标志物 来自肿瘤学研究信息交换网络（ORIEN）的测序（WES）数据，以及 电子健康记录（EHR）系统，即英国生物库和范德比尔特大学生物库（BioVU）。 我们组建了一个多学科团队，以实现以下三个具体目标：1）。识别和 在基线时验证代谢组学生物标志物，以区分发生与未发生的MM患者 卡非佐米相关HF。2）。鉴别和复制与卡非佐米相关HF相关的生殖系遗传变异 MM患者中。3）。建立并验证MM患者中卡非佐米相关HF的预测模型。 预计拟议的工作将提供工具，使MM患者的心脏毒性风险分层 基于药物基因组学和代谢组学生物标志物，并为这些生物标志物的临床转化提供基础。 生物标志物。此外，这项工作还将提供重要的见解，在多大程度上遗传变异， 与蒽环类药物相关的心脏毒性相关的心血管事件也与卡非佐米相关的HF相关。最后， 我们的研究将潜在地导致当前临床实践的范式转变，以更好地预防心脏毒性， 并改善MM患者人群的结局。