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：
10460227
负责人：
DANIELA SALVEMINI
金额：
$ 52.98万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460227
关键词：
Address Adenosine Adenosine A3 Receptor Adenosine Kinase Adult Affect Agonist Animals Anti-Inflammatory Agents Antineoplastic Agents Attenuated Automobile Driving Behavioral Assay 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 Testing Therapeutic Therapeutic Intervention Translations Treatment Protocols Vertebral column adenosine receptor activation adverse drug reaction antagonist 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（Chemobrain）是与化学疗法治疗相关的常见神经毒性据估计，这会影响> 50％的患者。1然而，对CICI的基础机制知之甚少，而且没有FDA批准的预防或治愈性干预措施。因此，我们必须了解这种严重的不良药物反应的根本原因并确定新的治疗接近可能快速转化为诊所的潜力。我们的初步数据确定了关键机制基于腺苷依赖性代谢调节的中枢神经系统改变CICI，并且是新颖的目标治疗干预 - A3腺苷受体（AR）亚型（A3AR）。因此，我们的建议直接对PAR-16-275的反应：严重的不良药物反应研究。细胞外腺苷及其在ARS处的信号传导受依顿核苷酸酶和腺苷激酶的调节（ADK）。我们的初步结果在化学疗法的小鼠模型（顺铂和阿霉素）诱导的认知结果中损伤（CICI）表明，化学疗法改变了这些酶在认知中心的表达功能，包括前额叶皮层（PFC）和海马，并产生形态异常大脑（例如，在白质组织中，树突状树博和脊柱密度）。从机械上讲，我们发现化学疗法导致线粒体功能障碍，氧化和硝化应激（硝基氧化应激）中枢神经系统中的神经炎症。试验数据表明，化学疗法与NLRP3炎性体合作， 2值得注意的是，用高度选择性的A3AR补充腺苷信号传导激动剂显着减弱CICI，而运动活性却没有任何损失。自A3AR以来，这是非常令人兴奋的激动剂已经作为具有良好安全性的抗癌药的高级临床试验。尚不清楚A3AR激动剂的有益作用的基础的机制。我们假设那是：化学疗法破坏腺苷稳态，导致线粒体功能障碍和NLRP3- 驱动的神经炎症，最终导致认知障碍；补充腺苷信号传导有选择性的A3AR激动剂为CICI管理提供了有效的方法。这个建议使用多学科研究计划在调查时探索A3AR激动剂在CICI中的适用性潜在的保护机制。两个具体的目标将检验我们的假设。在AIM 1中，我们将测试化学疗法导致腺苷代谢失调和腺苷丧失的假设通向CICI的A3AR发出信号。在AIM 2中，我们将调查有益的基本行动方式 A3AR激动剂在保存认知功能方面的影响。我们的结果预计将提供新的分子通过确定CICI如何发展的洞察力，通过确定CICI如何发展腺苷-A3AR轴。预计这些研究将导致加快的“概念证明”研究开放为了满足这种高度未满足的医疗需求而进行新的翻译工作的大门。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial: Small molecules and biologics for future purinergic therapeutics.

社论：未来嘌呤能疗法的小分子和生物制剂。

DOI：
10.1007/s11302-023-09964-9
发表时间：
2023
期刊：
Purinergic signalling
影响因子：
3.5
作者：
Jacobson,KennethA;Salvemini,Daniela
通讯作者：
Salvemini,Daniela

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment.

DOI：
10.1172/jci157738
发表时间：
2022-09-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Squillace, Silvia;Niehoff, Michael L.;Doyle, Timothy M.;Green, Michael;Esposito, Emanuela;Cuzzocrea, Salvatore;Arnatt, Christopher K.;Spiegel, Sarah;Farr, Susan A.;Salvemini, Daniela
通讯作者：
Salvemini, Daniela

Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions.