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.

通过协调一致的努力，制定了针对急性辐射毒性的医疗对策， 辐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， 今天会发生这样的放射性事件。然而，急性辐射毒性的幸存者可能会发展 在暴露后数月至数年才出现临床上明显的延迟性损伤。心血管疾病是一种 电离辐射急性照射幸存者发病率和死亡率的主要来源。近十 日本原子弹爆炸幸存者中有10%死于心血管疾病， 涉及心脏照射的胸部放射治疗（RT）显示出1.7至2倍的心脏病 mortality.在几份报告中，接受RT治疗的食管癌患者表现出1/3的机会， 心包积液，治疗后发生率中位数仅为6个月。自从临床逆转 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， 尽早识别此类损伤，以便开始适当的干预至关重要。因此， 基于血液的测试，可以预测延迟辐射损伤的风险，例如在无症状的心脏中 辐射事故受害者的需要是一个迫切和未得到满足的需要。在此，我们建议延长SBIR第一阶段， 致力于进一步开发我们的基于多组学的生物标志物检测技术。在我们的第一阶段工作中， 下一篇：观察小组预测了暴露于伽马射线的小鼠模型中的辐射诱导的心脏病 (AUC>90%）。此外，还发现该组中的生物标志物在非人免疫缺陷病毒感染者的血清中失调。 灵长类动物（NHP）部分身体照射后3-6天。最后，在一组患者中验证了该小组， 食管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 进行严格的分析验证，然后在测试样品中进行盲态验证 从大鼠模型以及从NHP的精英幸存者队列纵向收集的样品（N=56， 在3个时间点采样）和食管癌患者队列（N=45）接受RT监测 用于心脏结局。将在所有步骤中寻求FDA生物标志物认证指南，以确保成功 按照评估商业化潜力的准则完成技术目标 基于生物标记的测试。这项研究的最终产品将是一个多组学生物标志物测定， 详细的标准操作程序和软件算法（MetaboWatch），图形用户 界面提供生物标志物数据和总体风险评分的解释。交叉验证 生物样本的光谱将建立和巩固用于生物监测的性能测量 在独立的临床研究中心进行检测，以供将来临床使用。可将该监测分析用作一个标准- 单独的风险评估测试或与常规临床筛查结合。在第二阶段取得成功后， 研究，我们将进行临床评价，以支持FDA批准上市的IIB期工作。