A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy

描述(申请人提供)：化疗诱导的周围神经病(CIPN)伴随慢性神经病理性疼痛是广泛使用的抗肿瘤药物在紫杉烷(例如紫杉醇)、铂络合物(例如奥沙利铂)、长春新碱(例如长春新碱)和蛋白酶体抑制剂(例如Bortezomib)类别1-3中的主要剂量限制毒性。CIPN是减少剂量的最常见原因之一，否则是一种挽救生命的疗法。2-7通过确定可立即转移到临床的治疗靶点来解决这一重大的公共卫生问题具有极其重要的意义。我们已经确定了 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(CI-IBMECA)作为抗炎和抗肿瘤药物正在进行高级临床试验。9，10这项建议强调了一项多学科研究计划，该计划建立在我们初步数据的基础上，以探索A3AR激动剂在CIPN中的适用性，同时研究其潜在的保护机制(S)。通过IB-MECA，三个特定的目标将检验我们的中心假设：A3AR激动剂是治疗由化疗药物(紫杉醇、奥沙利铂和Bortezomib)引起的CIPN的有效药物，具有不同的抗肿瘤作用机制，其有益作用发挥在周围感觉传入(PSA)神经元和/或脊髓水平。在目标1中，我们将测试1)IB-MECA是否阻断和逆转神经病理性疼痛，2)IB-MECA是否通过药理学和遗传敲除方法特异性地介导A3AR机制，3)IB-MECA的作用基础是潜在的中枢和外周部位(S)，4)IB-MECA防止化疗引起的表皮内神经纤维退化和初级传入自发放电。在目标2中，我们将探讨IB-MECA通过保护PSA中的线粒体效应而减轻神经病理性疼痛的机制(S)。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/或脊髓中谷氨酸稳态的失调，这是已知对中枢敏化至关重要的过程。我们将集中在核因子B和MAPK(ERK1/2，p38)信号和胶质衍生的PRO(肿瘤坏死因子，IL1和IL6)/抗(IL10)炎性细胞因子，以及对脊髓谷氨酸转运体(神经元和胶质细胞)和胶质细胞谷氨酰胺合成酶表达和活性的影响。如果我们的假设成立，我们的结果有望为“概念验证”的使用提供药理学基础。 选择性A3AR激动剂作为治疗CIPN的新方法。从翻译的角度来看，这可能会导致对CIPN的IB-MECA进行“快车道”调查。这一令人兴奋的可能性强调了我们的研究提案在这一关键和未得到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，了解其基于机制的影响具有深远的基础科学和临床意义。

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.