A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy

A3AR 激动剂可预防化疗引起的疼痛性周围神经病变

基本信息

批准号：
9042993
负责人：
DANIELA SALVEMINI
金额：
$ 29.97万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042993
关键词：
Address Adenosine A3 Receptor Adverse effects Afferent Neurons Agonist Anti-Inflammatory Agents Anti-inflammatory Antibodies Attenuated Basic Science Bortezomib Chemotherapy-induced peripheral neuropathy Chronic Clinic Clinical Clinical Research Clinical Trials Complex Data Development Disease Dose Dose-Limiting Equilibrium Foundations Genetic Glutamate Transporter Glutamate-Ammonia Ligase Glutamates Health Homeostasis Hyperalgesia IL6 gene Inflammatory Interdisciplinary Study Interleukin-1 Interleukin-10 Investigation Knock-out Lead Life Link MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK11 gene MAPK14 gene MAPK3 gene Mediating Medical Mitochondria Modification Nerve Fibers Neurons Neuropathy Outcome Paclitaxel Pain Patients Peripheral Peripheral Nervous System Diseases Peroxonitrite Platinum Process Production Proteasome Inhibitor Proteins Public Health Purinergic P1 Receptors Quality of life Research Proposals Sensory Site Spinal Spinal Cord Stress Synapses TNF gene Testing Therapeutic Time Toxic effect Translations Vinca Alkaloids Vincristine allodynia analog antitumor effect attenuation base bench to bedside central sensitization chemotherapy chronic neuropathic pain cytokine drug efficacy genetic approach mitochondrial dysfunction neoplastic neuroinflammation neurotransmission new therapeutic target nitration novel strategies novel therapeutic intervention oxaliplatin painful neuropathy prevent targeted treatment taxane therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of widely used antitumoral agents in the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) & proteasome-inhibitor (e.g., bortezomib) classes.1-3 Thus, CIPN is one of most common causes of dose reduction & discontinuation of what is otherwise a life-saving therapy.2-7 Addressing this major public health issue by identifying therapeutic targets with immediate potential translation to the clinic is of paramount significance. We have identified A3 adenosine receptor (A3AR) agonism as a new viable therapeutic strategy for treating or reversing CIPN (Appendix 1 & ref8). Noteworthy, the selective A3AR agonists IB-MECA & its 2-chloro analogue (Cl-IBMECA) are in advanced clinical trials as antiinflammatory & antitumor agents.9,10 This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore the breadth of A3AR agonist applicability in CIPN while investigating underlying protective mechanism(s) of action. Using IB-MECA, three Specific Aims will test our central hypothesis: A3AR agonists are effective therapeutics in CIPN caused by chemotherapeutics with distinct antitumor mechanisms of action (paclitaxel, oxaliplatin & bortezomib) with beneficial effects exerted at the level of the peripheral sensory afferent (PSA) neuron &/or spinal cord. In Aim 1, we will test if 1) IB-MECA blocks & reverses neuropathic pain, 2) the effects of IB-MECA are specific to an A3AR mediated mechanism using pharmacological & genetic knockout approaches, 3) potential central & peripheral site(s) of action underlie IB-MECA's action & 4) IB-MECA prevents chemotherapy-evoked degeneration of intraepidermal nerve fibers & primary afferent spontaneous discharge. In Aim 2, we will investigate the mechanism(s) whereby IB-MECA attenuates neuropathic pain through mitoprotective effects in PSA. Finally, in Aim 3, we will investigate if IB-MECA's effects include attenuating neuroinflammation &/or the dysregulation of glutamate homeostasis in the spinal cord, processes known to be essential to central sensitization. We will focus on NF�B & MAPK (ERK1/2, p38) signaling & glial-derived pro (TNF�, IL1�, & IL6)/anti (IL10)-inflammatory cytokines, as well as, the effects on the expression & activities of spinal glutamate transporters (neuronal & glial) & glial glutamine synthetase. If our hypothesis holds true, the outcome of our results are anticipated to provide the pharmacological rationale for "proof-of-concept" for the use of selective A3AR agonists as a new approach in CIPN. From a translational perspective, this could conceivably lead to a "fast track" investigation of IB-MECA for CIPN. This exciting possibility underscores the immediate clinical impact that our research proposal may have in this critical & unmet medical setting. Given the breadth of disorders impacted by A3AR agonists understanding their mechanism-based effects has far-reaching basic science & clinical implications.

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）伴随慢性神经性疼痛是广泛使用的抗肿瘤药物的主要剂量限制性毒性，包括紫杉烷（例如紫杉醇）、铂络合物（例如奥沙利铂）、长春花生物碱（例如长春新碱）和蛋白酶体抑制剂（例如硼替佐米）类别。1-3 因此，CIPN 是减少剂量和停止挽救生命的治疗的最常见原因之一。2-7 通过确定可立即转化为潜在治疗效果的治疗靶点来解决这一重大公共卫生问题。我们已经确定了临床的重要性。 A3 腺苷受体 (A3AR) 激动剂作为治疗或逆转 CIPN 的新的可行治疗策略（附录 1 和参考文献 8）值得注意的是，选择性 A3AR 激动剂 IB-MECA 及其 2-氯类似物 (Cl-IBMECA) 正在进行高级临床试验。作为抗炎和抗肿瘤药物。9,10 该提案强调了一项多学科研究计划，该计划以我们的初步数据为基础，探索 A3AR 激动剂的广度在研究潜在的保护作用机制时，使用 IB-MECA，三个具体目标将检验我们的中心假设：A3AR 激动剂是具有不同抗肿瘤作用机制的化疗药物（紫杉醇、奥沙利铂和硼替佐米）引起的 CIPN 的有效治疗方法。）在外周感觉传入（PSA）神经元和/或脊髓水平上发挥有益作用在目标 1 中，我们将测试是否。 1) IB-MECA 阻断并逆转神经病理性疼痛，2) IB-MECA 的作用特定于使用药理学和基因敲除方法的 A3AR 介导机制，3) 潜在的中枢和外周作用位点是 IB-MECA 作用的基础4) IB-MECA 预防化疗引起的表皮内神经纤维变性和初级传入自发放电在目标 2 中，我们将研究其机制。因此，IB-MECA 通过 PSA 的线粒体保护作用减轻神经性疼痛。最后，在目标 3 中，我们将研究 IB-MECA 的作用是否包括减轻神经炎症和/或脊髓谷氨酸稳态失调，这些过程已知对中枢神经系统至关重要。我们将重点关注 NF�B 和 MAPK（ERK1/2、p38）信号传导和胶质细胞衍生蛋白。（TNF、IL1 和 IL6）/抗（IL10）炎症细胞因子，以及对脊髓谷氨酸转运蛋白（神经元和神经胶质）和神经胶质谷氨酰胺合成酶的表达和活性的影响如果我们的假设成立，我们的结果预计将为该用途提供“概念验证”的药理学原理从转化的角度来看，这可能会导致针对 CIPN 的 IB-MECA 的“快速通道”研究，这种令人兴奋的可能性强调了我们的研究提案可能对此产生的直接临床影响。鉴于 A3AR 激动剂影响的疾病范围广泛，了解其基于机制的作用具有深远的基础科学和临床意义。