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.

共同努力已导致针对急性放射毒性的医学对策的发展 放射性事故或核恐怖主义的受害者，从而大大增加生存机会 今天就发生了这样的放射性事件。然而，急性辐射毒性的幸存者可能会出现 延迟性损伤在接触后数月至数年才会出现临床症状。心血管疾病就是其中之一 急性电离辐射幸存者发病和死亡的主要来源。近十 日本原子弹爆炸幸存者的百分比死于心血管疾病，而癌症患者则死于 涉及心脏暴露的胸部放射治疗 (RT) 会使心脏病风险增加 1.7 至 2 倍 死亡。在几份报告中，接受放疗治疗食管癌的患者有三分之一的机会 心包积液的中位发生时间仅为治疗后 6 个月。由于临床逆转 辐射诱发的心血管疾病即使不是不可能，也是很困难的，一旦幸存者出现症状， 尽早发现此类伤害至关重要，以便可以开始适当的干预措施。因此，可用性 基于血液的测试可以预测延迟辐射损伤的风险，例如无症状患者的心脏损伤 辐射事件受害者的需求是一项紧迫且未得到满足的需求。在此，我们建议延长 SBIR 第一阶段 致力于进一步开发我们基于多组学的 CardioWatch 生物标志物测定。在我们第一阶段的努力中， CardioWatch 小组在暴露于伽马射线的小鼠模型中预测了辐射诱发的心脏病 （AUC>90%）。此外，还发现该组中的生物标志物在非人类血清中失调 灵长类动物 (NHP) 部分身体照射后 3-6 天。最后，该小组在一组患者中得到了验证 食管癌放疗后出现心脏并发症。在拟议的第二阶段研究中，我们将 对 CardioWatch 测定进行严格的分析验证，然后对测试样本进行盲法验证 来自大鼠模型以及从 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）和一组接受 RT 监测的食管癌患者 (N=45) 对于心脏结果。将在所有步骤中寻求 FDA 生物标志物资格指导，以确保成功 完成符合评估商业化潜力指南的技术目标 基于生物标记的测试。这项研究的最终产品将是一种多组学生物标志物测定，其中包含 详细的标准操作程序和带有图形用户的软件算法（MetaboWatch） 界面提供生物标志物数据和总体风险评分的解释。之间的交叉验证 生物样本谱将建立并巩固 CardioWatch 的性能测量 在独立的临床地点进行测定以供将来的临床使用。 CardioWatch 测定可用作标准 单独进行风险评估测试或与常规临床筛查结合使用。继第二阶段成功之后 研究后，我们将进行临床评估，以支持 FDA 在 IIB 期工作中批准上市。