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.

与癌症疗法相关的心脏毒性是一个重大的临床问题，NCI和NHLBI共同拥有 发行PA-19-112以刺激应用，目的是减轻心血管功能障碍，同时优化 癌症的结果。与蛋白酶体抑制剂Carfilzomib有关的心脏毒性，例如心力衰竭（HF） 是一个越来越认识的不良事件，导致症状负担和不良结果 多发性骨髓瘤（MM）患者。考虑到与Carfilzomib相关的知识差距 心脏毒性，一种药物基因组学方法可以鉴定这种药物基因组/代谢组生物标志物 不良反应，并提供了改善癌症患者心血管结局的机会 个性化的方式。我们的长期目标是确定和制定针对癌症患者的预防策略 在服用这种心脏毒性治疗之前，与Carfilzomib相关的心脏毒性的高风险 预防或最小化这种风险。我们的中心假设是与Carfilzomib相关的特征生物标志物 通过询问多摩学数据，可以辨别心脏毒性。我们的初步结果证明了 这种方法的可行性，并建议与Carfilzomib相关的代谢组和蛋白质组学特征 HF与非癌症患者的HF相似。更重要的是，我们的发现支持以下假设 Carfilzomib和Anthracyclines引起的心脏毒性的发展有重叠的途径。 该应用的总体目标是识别和验证代谢组和药物基因组学 MM患者使用多词的生物标志物与MM患者中的HF生物标志物和现有的外显子 肿瘤学研究信息交换网络（ORIEN）的测序（WES）数据 电子健康记录（EHR）系统，即范德比尔特大学（BIOVU）的英国生物银行和生物银行。 我们组建了一个多学科团队，以执行以下三个特定目标：1）。识别和 在基线上验证代谢组生物标志物，以区分发展而不发展的MM患者 与Carfilzomib相关的HF。 2）。识别并复制与Carfilzomib相关的HF相关的种系遗传变异 在MM患者中。 3）。在MM患者中，建立和验证与Carfilzomib相关的HF的预测模型。 预计拟议的工作将提供工具以实现MM患者的心脏毒性风险分层 基于药物基因组和代谢组生物标志物，并为这些临床翻译提供了基础 生物标志物。此外，这项工作还将提供重要的见解，以了解遗传变异的程度 与蒽环类药物相关的心脏毒性相关，也与Carfilzomib相关的HF相关。最终， 我们的研究可能会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患者人群的预后。