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

摘要 用许多广泛使用的化学治疗剂治疗的癌症患者，包括紫杉醇（PAC）和紫杉醇。 奥沙利铂（OXA）经常发生化疗诱导的周围神经病变（CIPN），可能导致 剂量降低、给药方案改变和治疗终止。在某些患者中，急性外周 神经病变（PN）可转变为慢性PN，持续时间远远超过化疗终止。目前， 没有预防CIPN的药物，并且现有镇痛剂的治疗性“标签外”使用是无效的。 最近的证据表明，热敏TRP离子通道家族的一个成员负责 由受影响的感觉神经元引起的疼痛产生。我们已经确定了瞬时受体电位， 亚家族A，成员1（TRPA 1），作为新的镇痛药物治疗或预防CIPN的有前途的目标。 TRPA 1被有害的寒冷和ROS激活，与发现的快速诱导的冷异常性疼痛症状一致 CIPN患者该提案的目标是开发一种基于新分子的新治疗方法， 靶向这一参与对CIPN的急性和慢性反应的关键分子的机制。我们建议 开发一种新的治疗性TRPA 1小分子功能性拮抗剂，用于治疗CIPN。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，感觉神经纤维末梢检测并传递 神经损伤引起的痛觉和痛觉过敏。PAC或OXA处理诱导上调 和TRPA 1的致敏作用。我们的初步体内数据显示TRPA 1拮抗剂逆转神经病理性 平移紫杉醇-CIPN模型中的疼痛行为。总体目标是开发TRPA 1拮抗剂， 与PAC或OXA联合使用，可有效阻断CIPC期间的TRPA 1激活。 我们的研究将首先确定TRPA 1拮抗剂抑制PAC-和OXA-的效力和功效。 在培养的DRG神经元中诱导激活。其次，三种TRPA 1拮抗剂的药代动力学将 以使体内功效研究的剂量选择成为可能。第三，TRPA 1的剂量-反应曲线 将使用急性和慢性方法在翻译大鼠PAC-和OXA-CIPN模型中测定拮抗剂 剂量。最终目的是确定在PAC或OXA之前和期间是否给予TRPA 1拮抗剂 给药可以防止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II期完整开发项目所需药理学特性的候选药物。

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.