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

项目摘要（摘要） 癌症治疗引起的心血管并发症是癌症发病率和死亡率的主要原因 患者和幸存者。传统癌症疗法的毒性，如蒽环类药物，以及更多 选择性靶向治疗，已被充分记录和心脏损伤的潜在机制 彻底研究。心血管毒性的一个新的，非常有前途的治疗，免疫检查点抑制剂 (ICI)，并没有很好地界定，并提出了一个重大的诊断和病人管理的挑战，心脏病， 肿瘤学家此外，越来越多地使用的化疗/ICI组合疗法的心脏损伤尚未被发现。 进行了任何重大程度的调查。由于无创性的优势，心脏成像是最 用于在癌症治疗期间和之后监测心脏功能的常用技术，但目前的方法 缺乏分子特异性且不能足够早地检测心脏毒性以允许及时干预， 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。使用早期靶向药物的正电子发射断层扫描（PET）成像 心血管毒性的指标可以提供一个强大的和高度特异性的非侵入性工具，用于检测 与传统以及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，具有独特的能力，可评估ICI和ICI的病理生理学核心。 和蒽环类药物相关的心脏毒性-激活的T细胞和心肌细胞中的线粒体功能 - 作为早期诊断和监测ICI相关心脏毒性的成像生物标志物， 以及化疗。本项目的近期目标是研究心肌细胞与心肌细胞之间的相关性。 [18F]F-AraG摄取和驱动ICI和蒽环类药物（多柔比星）心脏毒性的过程。长期 目标是开发一种高度敏感和特异的技术，以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个独特的和临床准备成像方法， 解决了心脏肿瘤学的一个关键临床问题：早期心脏毒性的无创检测 阶段，以允许治疗干预和降低心血管风险。所提出的成像 该技术适用于评估与不同癌症治疗相关的心脏毒性，包括ICI- 以及目前不存在诊断方法的组合化学/ICI方法。

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.