Development of Pirenzepine for CIPN

项目总结 化疗所致的周围神经病变(CIPN)是一种衰弱的并发症，可由使用 化疗药物的数量，并限制了用这些药物治疗癌症的剂量和持续时间 探员们。多达40%的接受化疗的癌症患者描述了某种形式的CIPN，具有感觉性 神经病占主导地位。症状不一，从表示感觉丧失的刺痛和麻木到 痛性神经病，如痛觉过敏和自发性射血疼痛。美国临床学会 肿瘤学没有对CIPN的预防提出建议，只提供了适度的 推荐使用度洛西汀治疗，这是一种治疗症状的5-羟色胺-去甲肾上腺素再摄取抑制剂 减轻痛苦。 WinSanTor的创始人在感觉神经元中发现了一种新的动态平衡机制，该机制限制了 线粒体功能，可以用来改善能量供应，逆转和防止神经损伤 在CIPN中。我们已经证明了M受体1(M1R)的信号极限 线粒体的活性和拮抗M1R增加了线粒体的整体呼吸能力。 此外，我们还观察到M1R拮抗剂哌仑西平可以预防由 化疗药物。这一第一阶段STTR项目的目标是评估 哌仑西平作为CIPN干预增强神经元AMPK活性和恢复神经元能量能力 在不妨碍化疗微管稳定特性的情况下预防或逆转神经病 紫杉醇。为此，我们的具体目标是： 具体目的1.评价紫杉醇在哌仑西平存在下的杀瘤活性。 具体目的2.检测哌仑西平对小鼠紫杉醇CIPN模型的疗效。 本文提出的研究将进一步推进哌仑西平的临床前开发，这可能是第一个- 预防和/或逆转CIPN的课堂治疗。

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication that can arise from use of a number of chemotherapeutics, and which limits both the dose and duration of cancer treatments with these agents. Up to 40% of cancer patients treated with chemotherapy describe some form of CIPN, with sensory neuropathy being dominant. Symptoms vary from tingling and numbness indicative of sensory loss to aspects of painful neuropathy such as allodynia and spontaneous shooting pains. The American Society of Clinical Oncology makes no recommendations for the prevention of CIPN and provides only a moderate recommendation for treatment with duloxetine, a serotonin-norepinephrine reuptake inhibitor for symptomatic relief of pain. WinSanTor’s founders have uncovered a new homeostatic mechanism in sensory neurons that constrains mitochondrial function, which can be exploited to improve energy supply to reverse and to prevent nerve damage in CIPN. We have demonstrated that the muscarinic acetylcholine type 1 receptor (M1R) signaling limits mitochondrial activity and that antagonizing M1R increases the overall respiratory capacity of mitochondria. Additionally, we have observed that the M1R antagonist pirenzepine can prevent the neuropathy induced by chemotherapeutic agents. The goal of this Phase I STTR project is to assess the therapeutic potential of pirenzepine as a CIPN intervention that enhances neuronal AMPK activity and restores neuronal energy capacity to prevent or reverse neuropathy without impeding the chemotherapeutic microtubule-stabilizing properties of paclitaxel. To this end our Specific Aims are: Specific Aim 1. Assess the tumoricidal activity of paclitaxel in presence of pirenzepine. Specific Aim 2. Test efficacy of pirenzepine in mouse paclitaxel models of CIPN. The studies proposed herein will advance further pre-clinical development of pirenzepine as a potentially first- in-class therapy for preventing and/or reversing CIPN.