A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity

认知障碍(化疗)是一种与化疗相关的常见神经毒性。 据估计，这会影响50%的患者。1然而，人们对CiCi背后的机制知之甚少。 目前还没有FDA批准的预防性或治疗性干预措施。因此我们当务之急是 了解这种严重药物不良反应的潜在原因，并确定新的治疗方法 具有快速转化到临床的潜力的方法。我们的初步数据确定了一个关键的机制 基于腺苷依赖代谢调节的中枢神经系统改变和一个新的靶点来驱动CiCi 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的回应：严重药物不良反应研究。 胞外腺苷及其在AR上的信号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)诱导的小鼠认知模型中的初步结果 损伤(CiCi)显示化疗改变了认知中枢中这些酶的表达 功能，包括前额叶皮质(PFC)和海马体，并产生形态异常 大脑(例如，白质组织、树突分枝和脊椎密度)。从机械上讲，我们 发现化疗导致线粒体功能障碍、氧化和硝化应激(亚硝酸盐应激) 中枢神经系统的神经炎症。试验数据表明，化疗激活了NLRP3炎症小体， 这在IL1β的形成中至关重要。2值得注意的是，用高选择性的A3AR补充腺苷信号 激动剂可显著减弱CiCi，但不影响运动能力。这是非常令人兴奋的，因为A3AR 激动剂已经作为具有良好安全性的抗癌药物进入了高级临床试验。 支持A3AR激动剂有益效果的机制尚不清楚。我们假设 那就是：化疗破坏腺苷稳态，导致线粒体功能障碍和NLRP3- 导致最终导致认知障碍的神经炎症；补充腺苷信号 选择性A3AR激动剂的应用为CCI的治疗提供了一条有效的途径。这项建议 使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(S)。两个具体目标将检验我们的假设。在目标1中，我们将测试 认为化疗导致腺苷代谢失调和腺苷丢失的假说 在A3AR上发出信号，通向CiCi。在目标2中，我们将调查利益背后的行动模式 A3AR激动剂在保护认知功能中的作用。我们的结果有望为我们提供新的分子 这些见解将通过确立CiCi的特定角色来促进我们对CiCi发展的理解 腺苷-A3AR轴。这些研究预计将导致加快“概念证明”研究，开启 在治疗CiCi方面进行新的转化努力，以满足这一高度未得到满足的医疗需求。

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.