Therapeutic TRPA1 Mechanism-Based Treatment of Chemotherapeutic-Induced Neuropathic Pain

摘要 癌症患者接受许多广泛使用的化疗药物治疗，包括紫杉醇(PAC)和 奥沙利铂(OXA)，经常发展为化疗引起的周围神经病变(CIPN)，可能导致 减少剂量、改变给药计划和终止治疗。在一些患者中，急性外周 神经病变(PN)可以转变为慢性PN，持续到化疗结束后很久。目前， 目前还没有预防CIPN的药物，现有止痛药的治疗性“标签外”使用也是无效的。 最近的证据表明，温度敏感的色氨酸离子通道家族的一个成员负责 由受影响的感觉神经元产生的疼痛。我们已经确定了瞬时受体电势， A亚家族成员1(TRPA1)，有望成为治疗或预防CIPN的新型止痛药的靶点。 TRPA1被伤寒和ROS激活，与快速诱导的感冒超敏症状一致 在CIPN患者中。这项提议的目标是开发一种新的治疗方法，基于一种新的分子 针对这一关键分子的机制，涉及对CIPN的急性和慢性反应。我们建议 开发一种新型的治疗CIPN的TRPA1小分子功能拮抗剂。TRPA1 受体通道在感觉神经纤维末梢上具有高度特异性的功能，它检测和传递 对神经损伤的反应有痛感和痛觉过敏。PAC或OXA治疗诱导细胞表达上调 和对TRPA1的增敏作用。我们的初步活体数据显示，TRPA1拮抗剂逆转了神经病变 平移紫杉醇-CIPN模型中的疼痛行为。总体目标是开发一种TRPA1拮抗剂 与PAC或OXA联合使用，可有效阻断CIPN期间TRPA1的激活。 我们的研究将首先确定TRPA1拮抗剂抑制PAC-和OXA-的效力和效果 诱导培养的背根神经节神经元激活。其次，三种TRPA1拮抗剂的药代动力学将 被确定为能够进行体内疗效研究的剂量选择。第三，TRPA1的剂量-反应曲线 拮抗剂将在翻译的大鼠PAC-和OXA-CIPN模型中使用急性和慢性 给药。最终目的是确定TRPA1拮抗剂是否在PAC或OXA之前和期间使用 给药可预防CIPN的诱导。第一阶段的最后一个里程碑是提供先进的临床前 具有第二阶段完整开发计划所必需的药理特性的候选人。

Abstract Cancer patients treated with many widely used chemotherapeutic agents, including paclitaxel (PAC) and oxaliplatin (OXA), frequently develop chemotherapy-induced peripheral neuropathy (CIPN) that may lead to dose reduction, dosing schedule changes and termination of treatment. In some patients, acute peripheral neuropathy (PN) can transition into chronic PN lasting well beyond termination of chemotherapy. Currently, there are no drugs to prevent CIPN and the therapeutic “off-label” use of existing analgesics is not effective. Recent evidence suggests that a member of the thermo-sensitive TRP ion channel family is responsible for pain generation arising from the affected sensory neurons. We have identified the transient receptor potential, subfamily A, member 1 (TRPA1), as a promising target for novel analgesic drugs to treat or prevent CIPN. TRPA1 is activated by noxious cold and ROS, consistent with rapidly induced cold allodynia symptoms found in CIPN patients. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets this key molecule involved in acute and chronic responses to CIPN. We propose to develop a novel, therapeutic small molecule functional antagonist of TRPA1 for the treatment of CIPN. TRPA1 receptor-channels serve a highly specific function on sensory nerve fiber endings that detect and transmit the sensations of pain and hyperalgesia in response to nerve injury. PAC or OXA treatment induces upregulation and sensitization of TRPA1. Our preliminary in vivo data shows that TRPA1 antagonists reverse neuropathic pain behaviors in a translational paclitaxel-CIPN model. The overall goal is to develop a TRPA1 antagonist delivered in combination with either PAC or OXA that is effective in blocking TRPA1 activation during CIPN. Our studies will first determine the potency and efficacy of TRPA1 antagonists to inhibit PAC- and OXA- induced activation in cultured DRG neurons. Second, the pharmacokinetics of three TRPA1 antagonists will be determined to enable dose selection for in vivo efficacy studies. Third, dose-response profiles for TRPA1 antagonists will be determined in translational rat PAC- and OXA-CIPN models using acute and chronic dosing. The final aim is to determine if a TRPA1 antagonist administered before and during PAC or OXA dosing can prevent induction of CIPN. The final Phase 1 milestone is to deliver an advanced preclinical candidate having pharmacological properties necessary for a full development program in Phase 2.