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

• 批准号: 9278122
• 负责人: DANIELA SALVEMINI
• 金额: $ 31.13万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278122
• 关键词: Address; Adenosine A3 Receptor; Adverse effects; Afferent Neurons; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antineoplastic Agents; Attenuated; Basic Science; Bortezomib; Chemotherapy-induced peripheral neuropathy; Clinic; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Complex; Data; Development; Disease; Dose; Dose-Limiting; Equilibrium; Foundations; Genetic; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Homeostasis; Hyperalgesia; IL6 gene; Inflammatory; Interdisciplinary Study; Interleukin-1; Interleukin-10; Investigation; Knock-out; Lead; Life; Link; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK14 gene; MAPK3 gene; Mediating; Medical; Mitochondria; Modification; Nerve Fibers; Neurons; Nitrates; Outcome; Paclitaxel; Pain; Patients; Peripheral; Peripheral Nervous System Diseases; Peroxonitrite; Pharmacology; Platinum; Process; Production; Proteasome Inhibitor; Proteins; Public Health; Purinergic P1 Receptors; Quality of life; Research Proposals; Savings; Sensory; Site; Spinal; Spinal Cord; Stress; Synapses; TNF gene; Testing; Therapeutic; Time; Toxic effect; Translations; Treatment Efficacy; Vinca Alkaloids; Vincristine; allodynia; analog; antitumor agent; antitumor effect; attenuation; base; bench to bedside; central sensitization; chemotherapy; chronic neuropathic pain; cytokine; drug efficacy; genetic approach; mitochondrial dysfunction; neuroinflammation; neurotransmission; new therapeutic target; nitration; novel strategies; novel therapeutic intervention; oxaliplatin; painful neuropathy; prevent; public health relevance; targeted treatment; taxane; therapeutic target

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）伴有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临床的治疗靶点来解决这一重大公共卫生问题至关重要。我们已经确定 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) 作为抗炎和抗肿瘤药物正在进行高级临床试验。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 激动剂在 CIPN 中的适用性，同时研究其潜在的保护机制。 行动。使用 IB-MECA，三个具体目标将检验我们的中心假设：A3AR 激动剂是化疗药物引起的 CIPN 的有效治疗方法，具有独特的抗肿瘤作用机制（紫杉醇、奥沙利铂和硼替佐米），在外周感觉传入 (PSA) 神经元和/或脊髓水平发挥有益作用。在目标 1 中，我们将测试 1) IB-MECA 是否能阻断和逆转神经性疼痛，2) IB-MECA 的作用是否特定于使用药理学和基因敲除方法的 A3AR 介导机制，3) IB-MECA 作用的潜在中枢和外周位点，以及 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 IB-MECA 通过 PSA 的线粒体保护作用减轻神经性疼痛的机制。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敏化至关重要。我们将重点关注 NF�B 和 MAPK（ERK1/2、p38）信号传导和神经胶质源性前（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的“概念验证”提供药理学原理 选择性 A3AR 激动剂作为 CIPN 的新方法。从转化的角度来看，这可能会导致 CI​​PN 对 IB-MECA 进行“快速通道”调查。这种令人兴奋的可能性强调了我们的研究计划在这个关键和未满足的医疗环境中可能产生的直接临床影响。鉴于 A3AR 激动剂影响的疾病范围广泛，了解其机制效应具有深远的基础科学和临床意义。

项目成果

Mitotoxicity in distal symmetrical sensory peripheral neuropathies.

• DOI: 10.1038/nrneurol.2014.77
• 发表时间: 2014-06
• 期刊: Nature reviews. Neurology
• 作者: Bennett GJ;Doyle T;Salvemini D
• 通讯作者: Salvemini D

Cancer and orofacial pain.

• DOI: 10.4317/medoral.21515
• 发表时间: 2016-11-01
• 期刊: Medicina oral, patologia oral y cirugia bucal
• 作者: Romero-Reyes M;Salvemini D
• 通讯作者: Salvemini D

Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase.

• DOI: 10.1016/j.pain.2013.07.032
• 发表时间: 2013-11
• 期刊: Pain
• 影响因子: 7.4
• 作者: Janes K;Doyle T;Bryant L;Esposito E;Cuzzocrea S;Ryerse J;Bennett GJ;Salvemini D
• 通讯作者: Salvemini D