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

• 批准号: 9761511
• 负责人: Cobi J Heijnen
• 金额: $ 54.84万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 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/9761511
• 关键词: Address; Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Adult; Affect; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; 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; Nitrates; Oral; Parahippocampal Gyrus; Patients; Pharmacology; Prefrontal Cortex; Preventive; Preventive Intervention; 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; protective effect; receptor; response; subventricular zone; time use; tumor; white matter

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.

认知功能障碍（chemobrain）是一种常见的与化疗相关的神经毒性 据估计，影响>50%的患者。1然而，对CICI的潜在机制知之甚少， 而且没有FDA批准的预防或治疗干预措施。因此，我们必须 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 具有快速转化为临床的潜力。我们的初步数据确定了一个关键机制 基于腺苷依赖性代谢调节的CNS改变驱动CICI， 治疗干预-A3腺苷受体（AR）亚型（A3 AR）。因此，我们的建议直接 PAR-16-275：严重药物不良反应研究。 胞外腺苷及其在AR的信号转导受胞外核苷酸酶和腺苷激酶的调节 （ADK）。我们在化疗（顺铂和阿霉素）诱导的认知功能障碍小鼠模型中的初步结果 CICI研究表明，化疗改变了这些酶在认知中枢的表达， 功能，包括前额叶皮层（PFC）和海马，并产生形态异常， 大脑（例如，在白色组织、树突状分支和棘密度中）。机械地，我们 发现化疗导致线粒体功能障碍，氧化和硝化应激（氮氧化应激） 和中枢神经系统的神经炎症。初步数据表明，化疗涉及NLRP 3炎性体， 2值得注意的是，用高选择性A3 AR补充腺苷信号传导， 激动剂显著减弱CICI而没有任何运动活性的损失。这是非常令人兴奋的，因为A3 AR 激动剂作为具有良好安全性的抗癌剂已经处于高级临床试验中。 支持A3 AR激动剂的有益作用的机制尚不清楚。我们假设 化疗破坏腺苷稳态，导致线粒体功能障碍和NLRP 3- 导致认知障碍的神经炎症;补充腺苷信号传导 与选择性A3 AR激动剂联合应用为CICI的治疗提供了一种有效的方法。这项建议 使用多学科研究计划，探索A3 AR激动剂在CICI中的适用性，同时研究 潜在的保护机制。两个具体目标将检验我们的假设。在目标1中，我们将测试 化疗引起腺苷代谢失调和腺苷损失的假说 在A3 AR处的信号传导导致CICI。在目标2中，我们将研究潜在的作用模式， A3 AR激动剂在保护认知功能中的作用。我们的研究结果有望提供新的分子 这些见解将通过建立CICI的具体作用来促进我们对CICI如何发展的理解。 腺苷-A3 AR轴。预计这些研究将加速“概念验证”研究， 为CICI治疗提供了一个新的转化努力，以满足这一高度未满足的医疗需求。