(PQ12) Peroxisome proliferator-activated receptor alpha agonists as potential treatment for chemotherapy-induced peripheral neuropathy

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Paclitaxel is a drug commonly used for the treatment of breast, lung, and ovarian cancer. Peripheral neuropathic pain (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 such as neurodegeneration; in fact, the current symptomatic therapies are frequently ineffective in mitigating the painful symptoms of CIPN in the majority of patients. Therefore, the identification of alternative forms of therapy is a crucial medical need. In this application we focus on agonists of peroxisome proliferator-activated receptor alpha (PPARα) as molecules of potential therapeutic value for suppression of CIPN induced by paclitaxel. The PPARα receptors are expressed by central and peripheral neuronal cells (dorsal root ganglia) involved in pain transmission and by macrophages and other cells immune involved in the inflammatory responses. In Aim 1, we will test whether fenofibrate, a clinically used non- selective and weak PPARα agonist, prevents CIPN in the mouse paclitaxel model in naïve mice. In Aim 2, we will characterize the potential of more selective novel PPARα agonists and modulators to prevent and suppress CIPN induced by paclitaxel in naïve mice. In Aim 3, we will assess the influence of these PPARα agonists on growth and susceptibility to chemotherapy (paclitaxel) in non-small cell lung tumors in culture, in patient derived tumor cells in culture and in tumor bearing animals. If effective treatment/prevention can be identified, it should be possible to extend the treatment of patients with drugs such as paclitaxel and platinum based compounds, as dose- dependent neuropathy will no longer limit the utility of these therapies.