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.

一致的努力导致了针对急性辐射毒性的医学对策发展 放射事故或核恐怖主义的受害者，从而大大增加了生存的机会 今天将发生这样的放射学事件。但是，急性辐射毒性的幸存者可能会发展 暴露后几个月至数年的临床明显受伤延迟。心血管疾病是一种 急性暴露于电离辐射的幸存者的发病率和死亡率的主要来源。将近十 日本原子弹幸存者中的百分比死于心血管疾病，正在接受的癌症患者 涉及心脏暴露的胸腔辐射疗法（RT）表现出1.7至2倍的心脏病 死亡。在几份报告中，用RT治疗食管癌的患者表现出1英寸3的机会 治疗后中位发生的心包积液仅为6个月。由于临床逆转 辐射引起的心血管疾病很难 尽早确定此类伤害至关重要，以便可以开始适当的干预措施。因此，可用性 基于血液的测试将预测延迟辐射损伤的风险，例如无症状的心脏中的心脏 辐射事件的受害者是紧急且未满足的需求。在此，我们建议扩展我们的SBIR阶段 努力进一步开发我们的基于多摩变的Cardiowch生物标志物测定法。在我们阶段的努力中， Cardiowatch面板预测辐射诱导的心脏病在暴露于伽马射线的小鼠模型中 （AUC> 90％）。此外，该面板中的生物标志物在非人类的血清中也失调 部分身体照射后3-6天（NHP）。最后，在一系列患者中验证了小组 RT用于食管癌后发展的心脏并发症。在拟议的II期研究中，我们将 对Cardiowatch分析进行严格的分析验证，然后在测试样品中盲目验证 来自大鼠模型以及来自NHP的精英幸存者队列的纵向收集的样品（n = 56， 在3个时间点取样）和一组食管癌患者（n = 45）接受RT进行监测 用于心脏结果。 FDA生物标志物资格指导将在所有步骤中寻求确保成功 符合评估商业化潜力的指南的技术目标完成 基于生物标志物的测试。这项研究的最终产品将是多摩斯生物标志物测定法 具有图形用户的详细标准操作程序和软件算法（Metabowatch） 界面提供了生物标志物数据和整体风险评分的解释。 a之间的交叉验证 生物样品的光谱将建立并巩固Cardiowatch的性能测量 在独立临床部位进行测定，以供将来的临床使用。 Cardiowatch测定法可以用作独立 单独使用风险评估测试或与常规临床筛查结合使用。在第二阶段成功之后 研究，我们将进行临床评估，以支持IIB阶段的FDA清除市场。