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.