A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity

A3AR 激动剂作为减轻化疗引起的神经毒性的新方法

基本信息

批准号：
10225344
负责人：
Robert Dantzer
金额：
$ 56.54万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225344
关键词：
Address Adenosine Adenosine A3 Receptor Adenosine Kinase Adult Affect Agonist Animals Anti-Inflammatory Agents Antineoplastic Agents Attenuated Automobile Driving Behavioral Assay Bioavailable Biological Assay Brain Cisplatin Clinic Clinical Trials Data Development Diagnosis Dose Doxorubicin Enzymes Event FDA approved Hippocampus (Brain)Homeostasis Impaired cognition Inflammasome Inflammatory Interdisciplinary Study Interleukin-1 Interleukin-10 Knockout Mice Lead Link Malignant Neoplasms Mediator of activation protein Medical Metabolic Metabolism Molecular Morphology Motor Activity Neurocognitive Neuroglia Neurons Oral Parahippocampal Gyrus Patients Pharmacology Prefrontal Cortex Preventive Process Public Health Purine Nucleosides Purinergic P1 Receptors Receptor Signaling Regulation Research Role Safety Serious Adverse Event Signal Pathway Signal Transduction Specificity Stress Structure Testing Therapeutic Therapeutic Intervention Translations Treatment Protocols Vertebral column adenosine receptor activation adverse drug reaction anti-cancer base chemobrain chemotherapy clinical translation cognitive function curative treatments cytokine density dentate gyrus extracellular genetic approach gray matter insight kinase inhibitor metabolomics mitochondrial dysfunction mouse model neuroinflammation neuron loss neurotoxicity new therapeutic target novel strategies novel therapeutic intervention preservation prevent preventive intervention protective effect receptor response subventricular zone time use tumor white matter

项目摘要

Cognitive impairment (chemobrain) is a common neurotoxicity associated with chemotherapy treatment that is estimated to affect >50% of patients.1 However, little is known about the mechanisms underlying CICI, and there have been no FDA-approved preventive or curative interventions. It is therefore imperative that we understand the underlying causes of this serious adverse drug reaction and identify novel therapeutic approaches with the potential for rapid translation to the clinic. Our preliminary data identify a key mechanism driving CICI based on CNS alterations of adenosine-dependent metabolic regulation and a novel target for therapeutic intervention - the A3 adenosine receptor (AR) subtype (A3AR). Therefore, our proposal directly responds to PAR-16-275: Serious Adverse Drug Reaction Research. Extracellular adenosine and its signaling at ARs are regulated by ectonucleotidases and adenosine kinase (ADK). Our preliminary results in mouse models of chemotherapy (cisplatin and doxorubicin)-induced cognitive impairment (CICI) reveal that chemotherapy altered the expression of these enzymes in centers of cognitive function, including the prefrontal cortex (PFC) and hippocampus, and produced morphological abnormalities in the brain (e.g., in white matter organization, dendritic arborization and spine density). Mechanistically, we found that chemotherapy led to mitochondrial dysfunction, oxidative and nitrative stress (nitroxidative stress) and neuroinflammation in CNS. Pilot data suggest that chemotherapy engaged the NLRP3 inflammasome, which is critical in IL1β formation.2 Noteworthy, supplementing adenosine signaling with highly selective, A3AR agonists significantly attenuated CICI without any loss in locomotor activity. This is highly exciting since A3AR agonists are already in advanced clinical trials as anticancer agents with a good safety profile. The mechanisms underpinning the beneficial effects of A3AR agonists are not known. We hypothesize that: chemotherapy disrupts adenosine homeostasis leading to mitochondrial dysfunction and NLRP3- driven neuroinflammation that culminate in cognitive impairment; supplementing adenosine signaling with selective A3AR agonists provides an effective approach for the management of CICI. This proposal uses a multidisciplinary research plan to explore the applicability of A3AR agonists in CICI while investigating underlying protective mechanism(s). Two Specific Aims will test our hypothesis. In Aim 1, we will test the hypothesis that chemotherapy causes the dysregulation of adenosine metabolism and loss of adenosine signaling at A3AR leading to CICI. In Aim 2, we will investigate the mode of action underlying the beneficial effects of A3AR agonists in preserving cognitive function. Our results are anticipated to provide new molecular insights that will advance our understanding of how CICI develops by establishing the specific role of the adenosine-A3AR axis. These studies are predicted to lead to expedited “proof of concept” studies opening the door to a new translational effort in the treatment of CICI to fulfill this highly unmet medical need.

认知障碍（化疗脑）是与化疗相关的常见神经毒性据估计，这会影响超过 50% 的患者。1 然而，人们对 CICI 的潜在机制知之甚少，目前还没有 FDA 的预防或治疗干预措施，因此我们必须采取这种措施。了解这种严重药物不良反应的根本原因并确定新的治疗方法我们的初步数据确定了具有快速转化为临床潜力的方法。基于中枢神经系统腺苷依赖性代谢调节的改变和新靶点驱动 CICI 治疗干预 - A3 腺苷受体 (AR) 亚型 (A3AR) 因此，我们直接提出建议。响应 PAR-16-275：严重药物不良反应研究。胞外腺苷及其在 AR 上的信号传导受核酸外切酶和腺苷激酶的调节（ADK）。我们在化疗（顺铂和阿霉素）诱导认知的小鼠模型中的初步结果。损伤（CICI）表明化疗会影响认知中枢这些酶的表达功能，包括前额皮质（PFC）和海马体，并产生形态异常大脑（例如，在白质组织、树突分枝和脊柱密度中）。发现化疗导致线粒体功能障碍、氧化和硝化应激（硝基氧化应激）试验数据表明化疗参与了 NLRP3 炎症体，这对于 IL1β 的形成至关重要。2 值得注意的是，用高选择性 A3AR 补充腺苷信号传导激动剂显着减弱 CICI 而没有任何运动活性损失，这是自 A3AR 以来非常令人兴奋的。激动剂作为具有良好安全性的抗癌药物已进入高级临床试验。 A3AR 激动剂有益作用的机制尚不清楚。认为：化疗破坏腺苷稳态，导致线粒体功能障碍和 NLRP3- 驱动神经炎症，最终导致认知障碍；补充腺苷信号传导；选择性A3AR激动剂为CICI的管理提供了有效的方法。在调查的同时，采用多学科研究计划探索 A3AR 激动剂在 CICI 中的适用性潜在的保护机制将检验我们的假设。在目标 1 中，我们将检验我们的假设。假设化疗导致腺苷代谢失调和腺苷损失在目标 2 中，我们将研究 A3AR 的信号传导导致 CICI。 A3AR 激动剂在维持认知功能方面的作用预计将提供新的分子。通过确立 CICI 的具体角色，我们将加深对 CICI 如何发展的理解。腺苷-A3AR 轴预计将导致加速“概念验证”研究。 CICI 治疗的新转化努力的大门，以满足这一高度未满足的医疗需求。