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

紫杉醇是一种常用于治疗乳腺癌、肺癌和卵巢癌的药物。 周围神经病理性疼痛(CIPN)是最常见和严重的不良反应之一 癌症患者接受紫杉醇治疗的效果。CIPN可以是一剂- 化疗的限制因素，导致过早终止治疗，从而 影响生存和生活质量。目前，还没有确定的治疗方法 解决潜在的致病机制，如神经退化；事实上， 目前的对症治疗在减轻疼痛方面往往无效 大多数患者出现CIPN症状。因此，可选方案的确定 各种形式的治疗是至关重要的医学需求。在本申请中，我们重点介绍了激动剂 作为潜在分子的过氧化物酶体增殖物激活受体α 紫杉醇抑制CIPN的治疗价值。PPARα受体 由中枢和外周神经细胞(背根神经节)表达，参与 通过巨噬细胞和其他免疫细胞参与疼痛的传递 炎症反应。在目标1中，我们将测试非诺贝特，一种临床使用的非 选择性和弱的PPARα激动剂，预防紫杉醇模型小鼠的CIPN 天真的老鼠。在目标2中，我们将表征更具选择性的新型PPARα的潜力 预防和抑制紫杉醇诱导的幼稚CIPN的激动剂和调节剂 老鼠。在目标3中，我们将评估这些PPARα激动剂对生长和 体外培养的非小细胞肺癌对化疗(紫杉醇)的敏感性 患者来源的肿瘤细胞在培养和荷瘤动物中。如果有效 可以确定治疗/预防，应该有可能延长治疗 服用紫杉醇和铂类化合物等药物的患者，剂量- 依赖型神经病将不再限制这些疗法的效用。

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.