Inhibition of NLRP3 inflammasome for the treatment of Chemotherapy-induced peripheral neuropathy

Summary Paclitaxel is a drug commonly used for the treatment of breast, lung, and ovarian cancer. Chemotherapy- induced peripheral neuropathy (CIPN) is one of the most common and serious adverse effects experienced by cancer patients treated with paclitaxel. CIPN can be a dose-limiting factor for chemotherapy, leading to premature termination of treatment, thereby influencing survival and quality of life. Currently, no therapies have been identified that address the underlying pathogenic mechanisms of CIPN. Therefore, the identification of alternative forms of therapy is a crucial medical need. This proposal focuses on a promising target: NLRP3 (which encodes NOD-, LRR- and pyrin domain-containing protein 3) inflammasome. Our preliminary data suggest for the first time that NLRP3 inflammasome contributes to CIPN produced by paclitaxel in mice. Paclitaxel treatment increased the expression levels of NLRP3, caspase-1 and IL-1β in the dorsal root ganglia (DRG) of mice. Furthermore, paclitaxel-induced neuropathic symptoms were completely absent in null mice lacking NLRP3 compared to wild type mice. Collectively, our preliminary results suggest that NLRP3 inflammasome inhibition represents a promising novel strategy for the treatment of CIPN. This project will test the central hypothesis that NLRP3 inflammasome activation contributes to paclitaxel-induced CIPN and that inhibition of NLRP3 inflammasome alleviates these effects. The main goal of the project is to determine whether dapansutrile, an oral selective NLRP3 inflammasome inhibitor currently in phase II clinical studies for the treatment of gout flares, alleviates and prevents paclitaxel-induced CIPN in a mouse model of naïve and tumor-bearing animals. We will determine the effects of dapansutrile after acute and chronic oral administration in mice treated with paclitaxel and cisplatin. We will then determine if dapansutrile reverses ongoing pain of paclitaxel-induced CIPN by capturing the motivation to seek relief using the conditioned place preference (CPP) test. Finally we will address if dapansutrile treatment would prevent CIPN while enhancing or at least not interefering with anti-tumor efficacy of paclitaxel in tumor- bearing mice. If successful, our project will provide a rationale for development of NLRP3 inflammasome- based medications to treat this side effect of cancer chemotreatment.