[18F]F-AraG as an imaging biomarker for early diagnosis and monitoring of cardiotoxicity related to doxorubicin and immune check point inhibitor therapy

[18F]F-AraG 作为成像生物标志物，用于早期诊断和监测与阿霉素和免疫检查点抑制剂治疗相关的心脏毒性

• 批准号: 10553684
• 负责人: Jelena Levi
• 金额: $ 69.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-21 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553684
• 关键词: Address; Animal Model; Anthracycline; Biological Markers; Blood; Blood Glucose; Cancer Etiology; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular system; Clinical; Detection; Development; Diagnostic; Diet; Doxorubicin; Early Diagnosis; Early identification; Evaluation; Functional disorder; Gender; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Image; Imaging Techniques; Immune checkpoint inhibitor; Immunotherapy; Impairment; Inflammatory; Intervention; Left Ventricular Ejection Fraction; Measurement; Mechanics; Mediating; Methods; Mitochondria; Molecular; Monitor; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial dysfunction; Myocarditis; Non-Invasive Detection; Normal Range; Oncologist; Oncology; Pathogenesis; Patients; Phase; Physiological; Positron-Emission Tomography; Prevention; Process; Quality of life; Recommendation; Research; Signal Transduction; Specificity; T cell infiltration; T-Cell Activation; Techniques; Therapeutic Intervention; Tissues; Toxic effect; Troponin I; Visualization; age related; cancer imaging; cancer therapy; cancer type; cardiovascular risk factor; checkpoint therapy; chemotherapy; clinic ready; cohort; combinatorial; comparative; diagnostic strategy; fluorodeoxyglucose; heart damage; heart function; heart imaging; human subject; imaging approach; imaging biomarker; imaging modality; immune cell infiltrate; immune function; improved; kinase inhibitor; mortality; prevent; targeted agent; targeted treatment; tool; uptake

Project Summary (Abstract) Cardiovascular complications caused by cancer therapy are a major cause of morbidity and mortality in cancer patients and survivors. Cardiotoxicity of traditional cancer therapies, such as anthracyclines, as well as more selective, targeted therapies, have been well documented and underlying mechanisms of cardiac injury thoroughly studied. Cardiovascular toxicity of a newer, very promising therapy, immune checkpoint inhibitors (ICI), is not well delineated and presents a significant diagnostic and patient management challenge for cardio- oncologists. Furthermore, cardiac damage of increasingly used chemo/ICI combinatorial therapies has not been investigated to any significant extent. Due to the advantage of being noninvasive, cardiac imaging is the most commonly used technique for monitoring cardiac function during and after cancer therapy, but current methods lack molecular specificity and are unable to detect cardiotoxicity sufficiently early to allow timely intervention and amelioration of cardiovascular risks. Inability of currently used imaging methods to detect subclinical cardiac involvement represents a major bottleneck for prevention and better management of cardiac complications in cancer patients and survivors. Positron emission tomography (PET) imaging using agents that target early indicators of cardiovascular toxicity could offer a powerful and highly specific noninvasive tool for detection of subclinical cardiac toxicity associated with traditional as well as ICI cancer therapy. We propose to investigate [18F]F-AraG, a PET agent with a unique ability to evaluate a pathophysiological centerpiece of both ICI and anthracycline-related cardiotoxicity - activated T cells and mitochondrial function in cardiomyocytes - as an imaging biomarker for early diagnosis and monitoring of cardiotoxicity associated with ICI as well as chemotherapy. The immediate goal of this project is to investigate the correlation between myocardial [18F]F-AraG uptake and processes that drive ICI and anthracycline (doxorubicin) cardiotoxicity. The long-term goal is development of a highly sensitive and specific technique to guide interventions in early, subclinical phases of cardiac dysfunction. The proposed research will deliver a unique and clinic-ready imaging approach to address a key clinical problem in cardio-oncology: noninvasive detection of cardiotoxicity at an early stage to allow therapeutic interventions and reduction of cardiovascular risks. The proposed imaging technique is applicable to assessment of cardiotoxicity associated with different cancer therapies, including ICI- and combinatorial chemo/ICI approaches for which no diagnostic approach currently exists.

项目概要（摘要） 癌症治疗引起的心血管并发症是癌症发病和死亡的主要原因 患者和幸存者。传统癌症疗法（例如蒽环类药物等）的心脏毒性 选择性、靶向治疗已被充分记录，并且是心脏损伤的潜在机制 彻底研究过。一种非常有前途的新型疗法——免疫检查点抑制剂的心血管毒性 （ICI），没有得到很好的描述，对心脏疾病的诊断和患者管理提出了重大挑战 肿瘤学家。此外，越来越多地使用化疗/ICI 组合疗法对心脏的损害尚未得到证实。 进行任何重大程度的调查。由于无创性的优点，心脏成像是最重要的 癌症治疗期间和治疗后监测心脏功能的常用技术，但目前的方法 缺乏分子特异性，无法及早检测心脏毒性以便及时干预和 改善心血管风险。目前使用的成像方法无法检测亚临床心脏疾病 参与是预防和更好地管理心脏并发症的主要瓶颈 癌症患者和幸存者。使用早期靶向药物进行正电子发射断层扫描 (PET) 成像 心血管毒性指标可以提供强大且高度特异性的非侵入性工具来检测 与传统和 ICI 癌症治疗相关的亚临床心脏毒性。我们建议调查 [18F]F-AraG，一种 PET 试剂，具有评估 ICI 病理生理学核心的独特能力 和蒽环类药物相关的心脏毒性 - 激活心肌细胞中的 T 细胞和线粒体功能 - 作为成像生物标志物，用于早期诊断和监测与 ICI 相关的心脏毒性 以及化疗。该项目的直接目标是研究心肌之间的相关性 [18F]F-AraG 摄取和过程驱动 ICI 和蒽环类药物（阿霉素）心脏毒性。长期来看 目标是开发一种高度敏感和具体的技术来指导早期、亚临床阶段的干预 心脏功能障碍。拟议的研究将提供一种独特且可供临床使用的成像方法 解决心脏肿瘤学的一个关键临床问题：早期无创检测心脏毒性 阶段以允许治疗干预和降低心血管风险。提议的成像 技术适用于评估与不同癌症治疗相关的心脏毒性，包括 ICI- 以及目前尚无诊断方法的组合化疗/ICI 方法。