CardioWatch: An Omics-Based Prediction Assay for Cardiac Late Effects ofAcute Radiation

CardioWatch：基于组学的急性辐射心脏迟发效应预测分析

• 批准号: 10759588
• 负责人: John B. Tyburski
• 金额: $ 99.57万
• 依托单位: NELSON SCIENTIFIC LABS LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759588
• 关键词: Acute; Adult; Advanced Development; Affect; Aftercare; Algorithmic Analysis; Algorithmic Software; Appearance; Biological; Biological Assay; Biological Markers; Biological Models; Blinded; Blood; Cancer Patient; Cardiac; Cardiovascular Diseases; Cause of Death; Characteristics; Chest; Clinical; Companions; Correlative Study; Data; Development; Diagnostic Reagent Kits; Dose; Early identification; Echocardiography; Ensure; Exhibits; Exposure to; Female; Funding; Future; Gamma Rays; Goals; Guidelines; Heart; Heart Diseases; Heart Injuries; Histologic; Inbreeding; Individual; Injury; Intervention; Ionizing radiation; Japanese; Kidney; Late Effects; Late Radiation Injury; Leg; Legal patent; Licensing; Lipids; Liquid Chromatography; Malignant neoplasm of esophagus; Marketing; Mass Spectrum Analysis; Measurement; Measures; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Nuclear; Organ Specificity; Outcome; Patients; Performance; Pericardial effusion; Phase; Plasma; Predisposition; Procedures; Proteins; Qualifying; Quality of life; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Toxicity; Radiation exposure; Radiation therapy; Rat Strains; Rattus; Reporting; Reproducibility; Resolution; Risk; Risk Assessment; Risk Estimate; Rodent; Roentgen Rays; Sampling; Serum; Severities; Small Business Innovation Research Grant; Software Tools; Source; Specificity; Sprague-Dawley Rats; Structure of parenchyma of lung; Survivors; Symptoms; Terrorism; Testing; Time; Tissues; University Hospitals; Validation; Work; acute toxicity; atomic bomb; biodosimetry; biomarker development; biomarker panel; clinical research site; cohort; commercialization; coronary fibrosis; cost effective; design; esophageal cancer patient; evaluation/testing; graphical user interface; heart function; insight; interest; irradiation; male; manufacture; medical countermeasure; minimally invasive; mortality; mouse model; multiple omics; multiple reaction monitoring; nonhuman primate; organ injury; phase 2 study; potential biomarker; predictive panel; predictive test; programs; radiation countermeasure; radiation response; research clinical testing; risk prediction; screening; success; validation studies

Concerted efforts have led to the development of medical countermeasures against acute radiation toxicity in victims of a radiological accident or nuclear terrorism, thereby significantly increasing the chance of survival if such a radiological event were to occur today. However, survivors of acute radiation toxicities may develop delayed injuries that become clinically apparent months to years after exposure. Cardiovascular disease is one of the main sources of morbidity and mortality in survivors of acute exposure to ionizing radiation. Nearly ten percent of Japanese atomic bomb survivors died of cardiovascular disease, and cancer patients undergoing thoracic radiation therapy (RT) involving cardiac exposures exhibit a 1.7- to 2-fold greater heart disease mortality. In several reports, patients treated with RT for esophageal cancer exhibited a 1-in-3 chance of pericardial effusion with median occurrence post-treatment of only 6 months. Since clinical reversal of radiation-induced cardiovascular disease is difficult, if not impossible once a survivor becomes symptomatic, it is critical to identify such injuries sooner so that the proper interventions can begin. Therefore, availability of a blood-based test that would predict risk for delayed radiation injuries such as in the heart in asymptomatic victims of radiation incidents is an urgent and unmet need. Herein, we propose to extend our SBIR Phase I work to further develop our multi-omics-based CardioWatch biomarker assay. In our Phase I effort, the CardioWatch panel predicted radiation-induced heart disease in mouse models of exposure to gamma-rays (AUC >90%). Furthermore, biomarkers in this panel were also found to be dysregulated in serum of non-human primates (NHP) 3-6 days after partial body irradiation. Finally, the panel was verified in a cohort of patients that developed cardiac complications following RT for esophageal cancer. In the proposed Phase II study, we will conduct a rigorous analytic validation of the CardioWatch assay, followed by blinded validation in test samples from rat models as well as longitudinally collected samples from an elite survivor cohort of NHPs (N=56, sampling at 3 time points) and a cohort of esophageal cancer patients (N=45) undergoing RT with monitoring for cardiac outcomes. FDA biomarker qualification guidance will be sought at all steps to ensure successful completion of technical objectives compliant with guidelines for evaluating commercialization potential of biomarker-based tests. The final product of this study will be a multi-omics biomarker assay replete with detailed standard operating procedures and a software algorithm (MetaboWatch) with a graphical user interface provides interpretation of biomarker data and an overall risk score. Cross-validation among a spectrum of biological samples will establish and solidify performance measurements for the CardioWatch assay at independent clinical sites for future clinical use. The CardioWatch assay could be used as a stand- alone risk assessment test or in conjunction with routine clinical screening. Following success in Phase II studies, we will perform clinical evaluations to support an FDA clearance to market in a Phase IIB effort.

同心协力制定了针对#年急性辐射毒性的医学对策 辐射事故或核恐怖主义的受害者，从而大大增加在下列情况下的生存机会 这样的辐射事件本应在今天发生。然而，急性辐射中毒的幸存者可能会发展成 在暴露几个月到几年后临床表现明显的延迟性损伤。心血管疾病是其中之一 急性电离辐射幸存者的发病率和死亡率的主要来源。将近十个人 %的日本原子弹幸存者死于心血管疾病，癌症患者正在接受 胸部放射治疗(RT)涉及心脏暴露，显示心脏病增加1.7到2倍 死亡率。在一些报告中，接受RT治疗的食道癌患者显示出1/3的机会 心包积液的中位发生率仅为治疗后6个月。自临床逆转以来 辐射引起的心血管疾病是困难的，如果不是不可能的话，一旦幸存者出现症状，它 及早发现这类伤害至关重要，以便能够开始适当的干预。因此，是否提供 基于血液的测试将预测延迟辐射损伤的风险，例如在无症状的情况下心脏 辐射事故受害者是一项迫切而又未得到满足的需求。在此，我们建议延长我们的SBIR第一阶段 致力于进一步开发我们基于多组学的心脏观察生物标记物检测。在我们的第一阶段工作中， 心脏观察小组预测伽玛射线暴露的小鼠模型中辐射诱发的心脏病 (AUC&GT；90%)。此外，这个小组中的生物标记物在非人类的血清中也被发现是失调的。 灵长类动物(NHP)局部照射后3-6天。最后，该小组在一组患者中进行了验证， 食道癌放疗后出现心脏并发症。在建议的第二阶段研究中，我们会 对心脏手表检测进行严格的分析验证，然后对测试样本进行盲法验证 从大鼠模型以及从NHP精英幸存者队列纵向收集的样本(N=56， 在3个时间点采样)和接受有监测的RT的食道癌患者队列(N=45) 对心脏功能的影响。将在所有步骤中寻求FDA生物标记物资格指南，以确保成功 完成符合评估商业化潜力指南的技术目标 基于生物标记物的测试。这项研究的最终产品将是一种多组学生物标记物分析， 图形用户的详细标准操作程序和软件算法(MetabWatch) 界面提供对生物标记物数据的解释和总体风险评分。之间的交叉验证 生物样品的光谱将建立和巩固心脏手表的性能测量 在独立的临床站点进行化验，以供将来临床使用。心脏手表检测可以作为一种标准- 单独进行风险评估测试或与常规临床筛查结合使用。继第二阶段取得成功后 在这项研究中，我们将进行临床评估，以支持FDA在IIB阶段的努力中批准上市。