[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: 10340980
• 负责人: Jelena Levi
• 金额: $ 72.84万
• 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/10340980
• 关键词: Address; Animal Model; Anthracycline; Biological Markers; Blood; Blood Glucose; Cancer Etiology; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular system; Cells; Clinic; Clinical; Detection; Development; Diagnostic; Diet; Doxorubicin; Early Diagnosis; Early identification; Evaluation; Functional disorder; Gender; Goals; Heart; Heart Diseases; Heart Injuries; Heart Mitochondria; Heart failure; Image; Imaging Techniques; Immune; Immune checkpoint inhibitor; Immunotherapy; Impairment; Infiltration; Inflammatory; Intervention; Lead; Left Ventricular Ejection Fraction; Measurement; Mechanics; Mediating; Methods; Mitochondria; Molecular; Monitor; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial dysfunction; Myocarditis; Non-Invasive Cancer Detection; Normal Range; Oncologist; Oncology; Pathogenesis; Patients; Phase; Physiological; Positron-Emission Tomography; Prevention; Process; Quality of life; Research; Signal Transduction; Specificity; T-Lymphocyte; Techniques; Therapeutic Intervention; Time; Tissues; Toxic effect; Troponin I; Tumor-infiltrating immune cells; age related; cancer imaging; cancer therapy; cancer type; cardiovascular risk factor; checkpoint therapy; chemotherapy; cohort; combinatorial; comparative; diagnostic strategy; fluorodeoxyglucose; heart damage; heart function; heart imaging; human subject; imaging approach; imaging biomarker; imaging modality; 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.

项目摘要（摘要） 癌症治疗引起的心血管并发症是癌症发病和死亡率的主要原因 患者和幸存者。传统癌症疗法的心脏毒性，例如蒽环类药物等等 选择性的，有针对性的疗法已被充分记录和基础心脏损伤机制 彻底研究。更新，非常有前途的疗法，免疫检查点抑制剂的心血管毒性 （ICI），没有很好地划定，并提出了对心脏的重大诊断和患者管理挑战 肿瘤学家。此外，越来越使用的化学/ICI组合疗法的心脏损伤尚未 在很大程度上进行了调查。由于具有无创的优势，心脏成像是最大的 在癌症治疗期间和之后监测心脏功能的常用技术，但是当前方法 缺乏分子特异性，无法足够早期检测到心脏毒性，无法及时干预和 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 参与代表了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。正电子发射断层扫描（PET）成像，使用早期靶向的剂 心血管毒性的指标可以提供强大而高度特定的无创工具，以检测 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，一种具有独特能力评估两种ICI病理生理核心的宠物代理 与蒽环类有关的心脏毒性 - 激活的T细胞和心肌细胞中的线粒体功能 - 作为用于早期诊断和监测与ICI相关的心脏毒性的成像生物标志物 以及化学疗法。该项目的直接目标是研究心肌之间的相关性 [18F] F-ARAG摄取和驱动ICI和Anthracycline（阿霉素）心脏毒性的过程。长期 目标是开发高度敏感和特定的技术，以指导早期的亚临床阶段干预措施 心脏功能障碍。拟议的研究将向 解决心脏肿瘤学的关键临床问题：早期对心脏毒性的无创检测 允许治疗干预措施并减少心血管风险的阶段。提出的成像 技术适用于与不同癌症疗法相关的心脏毒性的评估，包括ICI- 和组合化学/ICI方法目前尚无诊断方法。