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 (PPAR?) as molecules of potential therapeutic value for suppression of CIPN induced by paclitaxel. The PPAR? 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 PPAR? agonist, prevents CIPN in the mouse paclitaxel model in nave mice.
In Aim 2, we will characterize the potential of more selective novel PPAR? agonists and modulators to prevent and suppress CIPN induced by paclitaxel in nave mice.
In Aim 3, we will assess the influence of these PPAR? 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.
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and often dose- limiting complication of cancer therapy utilizing taxanes, platinum based drugs and newer agents such as bortezomib. Determining the modulatory role of an established and novel group of compounds acting as agonists of the peroxisome proliferator- activated receptor alpha (PPAR?) in chemotherapy-induced peripheral neuropathy represents a unique strategy for the development of treatments for prevention and/or reversal of CIPN. If successful, this application promises to have a significant impact on compliance and symptom management for cancer patients.
