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

(PQ12) 过氧化物酶体增殖物激活受体α激动剂作为化疗引起的周围神经病变的潜在治疗方法

• 批准号: 9750651
• 负责人: M. Imad Damaj
• 金额: $ 31.45万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750651
• 关键词: Acute; Address; Adverse effects; Agonist; Analgesics; Animal Model; Animals; Antiinflammatory Effect; Antineoplastic Agents; Bortezomib; Breast Cancer Treatment; Cancer Patient; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Clinical Trials; Data; Dose; Dose-Limiting; Drug Kinetics; Effectiveness; Electron Microscopy; Experimental Designs; Exposure to; FDA approved; Fatty Acids; Female; Fenofibrate; Fiber; Functional disorder; Generations; Growth; Human; Immune; Implant; Incidence; Inflammation; Inflammatory Response; Lead; Lewis Lung Carcinoma; Lipids; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mechanics; Medical; Metabolic; Metabolic Diseases; Microtubules; Mitochondria; Modeling; Mus; Nerve Degeneration; Nerve Fibers; Neurons; Neuropathy; New Agents; Non-Small-Cell Lung Carcinoma; Oral Ingestion; PPAR alpha; Paclitaxel; Pain; Pathogenicity; Pathologic Processes; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Platinum; Predisposition; Prevention; Progression-Free Survivals; Property; Quality of life; Randomized Clinical Trials; Reflex action; Rodent; Role; Severities; Spinal; Spinal Ganglia; Symptoms; Testing; Therapeutic; Tissues; Tumor-Derived; allodynia; antitumor effect; base; cancer complication; cancer therapy; chemotherapeutic agent; chemotherapy; density; dosage; effective therapy; experience; hypercholesterolemia; lipid metabolism; macrophage; male; neoplastic cell; novel; pain behavior; pain model; pain symptom; painful neuropathy; palmidrol; preference; premature; prevent; receptor; sciatic nerve; symptom management; taxane; therapy development; transmission process; treatment response; treatment strategy; tumor

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.

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（peripheral neuropathic pain，CIPN）是神经系统最常见和最严重的不良反应之一 紫杉醇治疗的癌症患者所经历的影响。CIPN可以是剂量- 化疗的限制因素，导致提前终止治疗，从而 影响生存和生活质量。目前，还没有发现任何治疗方法， 解决潜在的致病机制，如神经变性;事实上， 目前的对症治疗在减轻疼痛方面常常是无效的 大多数患者的CIPN症状。因此，替代品的识别 治疗形式是至关重要的医疗需求。在本申请中，我们集中于以下激动剂： 过氧化物酶体增殖物激活受体α（PPARα）作为潜在的 对紫杉醇诱导的CIPN抑制的治疗价值。PPARα受体 由中枢和外周神经元细胞（背根神经节）表达， 疼痛传递和巨噬细胞和其他细胞的免疫参与 炎症反应。在目标1中，我们将测试非诺贝特，一种临床上使用的非 选择性和弱的PPARα激动剂，在小鼠紫杉醇模型中阻止CIPN， 幼稚的老鼠在目标2中，我们将描述更具选择性的新型PPARα的潜力。 预防和抑制紫杉醇诱导的CIPN的激动剂和调节剂 小鼠在目标3中，我们将评估这些PPARα激动剂对生长的影响， 培养的非小细胞肺肿瘤对化疗（紫杉醇）的敏感性， 在培养物和荷瘤动物中的患者来源的肿瘤细胞。如果有效 治疗/预防可以确定，应该有可能扩大治疗 使用紫杉醇和铂类化合物等药物的患者， 依赖性神经病将不再限制这些疗法的效用。