[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。 病人和幸存者。传统癌症疗法的心脏毒性，如蒽环类药物以及更多 选择性的靶向治疗，已经被很好地记录下来，并且是心脏损伤的潜在机制。 彻底研究过。一种新的、非常有希望的治疗方法--免疫检查点抑制剂的心血管毒性 (ICI)，没有很好地描述，对心血管疾病的诊断和患者管理提出了重大挑战。 肿瘤学家。此外，越来越多的化疗/ICI联合治疗对心脏的损害还没有得到 在任何重大程度上都进行了调查。由于无创的优点，心脏成像是最重要的 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，无法足够早地检测到心脏毒性，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 介入是预防和更好地管理#年心脏并发症的主要瓶颈。 癌症患者和幸存者。使用早期靶向试剂的正电子发射断层扫描(PET)成像 心血管毒性指标可以提供一种强大且高度特异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，具有评估两个ICI的病理生理中心的独特能力 和蒽环类药物相关的心脏毒性激活T细胞和心肌细胞线粒体功能 -作为早期诊断和监测ICI AS相关心脏毒性的成像生物标志物 还有化疗。该项目的近期目标是研究心肌梗死与心肌梗死的相关性 [18F]F-Arag摄取和驱动ICI和蒽环素(阿霉素)心脏毒性的过程。长期的 目标是开发一种高度敏感和特定的技术，以指导早期、亚临床阶段的干预 心脏功能不全。这项拟议的研究将提供一种独特的、可用于临床的成像方法 解决心脏肿瘤学的一个关键临床问题：早期非侵入性检测心脏毒性 达到治疗干预和降低心血管风险的阶段。建议的成像 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- 以及目前尚不存在诊断方法的组合化疗/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.