(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。 周围神经性疼痛（CIPN）是最常见和最严重的不良反应之一 接受 CIPN 治疗的癌症患者所经历的效应可能与剂量有关。 化疗的限制因素，导致治疗提前终止，从而 目前，尚未发现影响生存和生活质量的治疗方法。 解决神经退行性疾病等潜在的致病机制； 目前的对症治疗常常无法有效减轻疼痛 大多数患者都有 CIPN 的症状，因此需要进行替代鉴别。 治疗形式是一项至关重要的医疗需求，在本申请中，我们重点关注激动剂。 过氧化物酶体增殖物激活受体 α (PPARα) 作为潜在分子 抑制紫杉醇诱导的 CIPN 的治疗价值。 由中枢和周围神经元细胞（背根神经节）表达，参与 疼痛传递以及巨噬细胞和其他参与免疫的细胞 在目标 1 中，我们将测试临床上使用的非诺贝特是否会抑制炎症反应。 选择性弱 PPARα 激动剂，可预防小鼠紫杉醇模型中的 CIPN 在目标 2 中，我们将描述更具选择性的新型 PPARα 的潜力。 激动剂和调节剂预防和抑制紫杉醇诱导的 CIPN 在目标 3 中，我们将评估这些 PPARα 激动剂对小鼠生长和发育的影响。 培养的非小细胞肺肿瘤对化疗（紫杉醇）的敏感性 培养物和荷瘤动物中的患者来源的肿瘤细胞如果有效。 可以确定治疗/预防，应该可以延长治疗 患者服用紫杉醇和铂类药物，化合物作为剂量- 依赖性神经病将不再限制这些疗法的效用。