Development of Pirenzepine for CIPN

项目摘要 化疗诱导的周围神经病变（CIPN）是一种使人衰弱的并发症，其可由使用化疗药物引起。 这限制了使用这些化疗药物的癌症治疗的剂量和持续时间 剂.高达40%的接受化疗的癌症患者描述了某种形式的CIPN， 神经病变占优势。症状从表明感觉丧失的刺痛和麻木到 疼痛性神经病，如异常性疼痛和自发性刺痛。The American Society of Clinical 肿瘤学不建议预防CIPN，仅提供适度的 推荐使用度洛西汀治疗，一种用于症状性 缓解疼痛。 WinSanTor的创始人发现了一种新的感觉神经元内稳态机制， 线粒体功能，可用于改善能量供应，以逆转和防止神经损伤 在CIPN。我们已经证明，毒蕈碱乙酰胆碱1型受体（M1 R）信号限制 线粒体活性，拮抗M1 R增加线粒体的总呼吸能力。 此外，我们已经观察到M1 R拮抗剂哌仑西平可以预防由M1 R诱导的神经病变。 化疗剂。该I期STTR项目的目标是评估 哌仑西平作为CIPN干预，增强神经元AMPK活性并恢复神经元能量容量 预防或逆转神经病而不妨碍化疗微管稳定特性， 紫杉醇。为此，我们的具体目标是： 具体目标1。评估紫杉醇在哌仑西平存在下的杀肿瘤活性。 具体目标2。在CIPN的小鼠紫杉醇模型中测试哌仑西平的功效。 本文提出的研究将进一步推进哌仑西平作为潜在的第一个- 用于预防和/或逆转CIPN的类内疗法。

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.