(PQ9) Mitigation of chemotherapy induced peripheral neuropathy

(PQ9) 减轻化疗引起的周围神经病变

• 批准号: 9101341
• 负责人: M. Imad Damaj
• 金额: $ 36.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101341
• 关键词: Adverse effects; Affective; Agonist; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Antineoplastic Agents; Attenuated; Bilateral; Bortezomib; Cancer Etiology; Cancer Patient; Cancer cell line; Carboplatin; Cells; Chemotherapy-induced peripheral neuropathy; Cisplatin; Complication; Development; Dimensions; Dose; Dose-Limiting; Down-Regulation; Effectiveness; Functional disorder; Growth; Hypersensitivity; Immune; Incidence; Inflammation; Inflammatory Response; Lead; Ligands; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mechanics; Mediating; Medical; Morphine; Motor; Mus; Nerve Degeneration; Neurons; Neuropathy; New Agents; Nicotinic Receptors; Non-Small-Cell Lung Carcinoma; Oral Administration; Paclitaxel; Pain; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Platinum; Predisposition; Prevention; Property; Quality of life; Rattus; Receptor Signaling; Reporting; Reservations; Rodent Model; Role; Sensory; Severities; Signal Pathway; Signal Transduction; Spinal Cord; Spinal Ganglia; Spine pain; Stimulus; Swimming; Symptoms; System; Testing; Thalidomide; Therapeutic; Tissues; Toxic effect; Vinca Alkaloids; Vincristine; Vinorelbine; acetylcholine receptor agonist; allodynia; alpha-bungarotoxin receptor; antitumor drug; attenuation; autonomic nerve; base; cancer cell; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; chronic neuropathic pain; clinically relevant; common treatment; cytokine; dosage; effective therapy; improved; macrophage; mechanical allodynia; mortality; mouse model; neoplastic cell; neuropathology; neurotoxic; novel; oxaliplatin; pain symptom; preference; premature; prevent; public health relevance; receptor; symptom management; targeted treatment; taxane; therapy development; transmission process; tumor; tumor growth

 DESCRIPTION (provided by applicant): Lung cancer is currently a leading cause of mortality. One of these serious neurotoxic side effects that develop in lung cancer patients receiving chemotherapeutic agents is chemotherapy-induced peripheral neuropathy (CIPN). Our proposal will be focused on CIPN induced by cisplatin and paclitaxel since these are two of the most effective and widely used chemotherapy drugs in the treatment of common cancers, including non- small cell lung cancer. CIPN can be a dose-limiting factor for chemotherapy or result in premature termination of treatment, thereby influencing survival and quality of life. Currently, there are no effective therapies that deal with the underlying pathogenic mechanisms such as neurodegeneration. In addition, the current symptomatic therapies that deal with painful symptoms of CIPN are generally ineffective. Therefore, the identification of alternative forms of therapy is a crucial medical need. In this application we will focus on nicotinic acetylcholine receptors (nAChRs) modulators, in particular α7 subtypes, as potential targets for treatment of CIPN. These receptors are expressed by central and peripheral neuronal cells (dorsal root ganglia) involved in pain transmission and by macrophages and other cells involved in the inflammatory responses. In Aim 1, we will test the ability of α7 nAChR silent agonists to prevent or ameliorate the development of peripheral neuropathy induced by cisplatin and paclitaxel, including well- defined neuropathologies that accompany CIPN. In Aim 2, we will test the α7 nAChR silent agonists in non-small cell lung cancer cell lines and patient derived tumor cells in culture as well as in tumor bearing mice to eliminate the possibility that these agents stimulate tumor growth or compromise the potency of chemotherapy (cisplatin and paclitaxel). In addition, suppression of CIPN by the α7 nAChR silent agonists will be confirmed in the tumor bearing mice. If effective treatment/prevention can be identified, it should be possible to treat patients or prolonged periods as dose-dependent neuropathy will not be a limiting toxicity and compliance as well as quality of life will be improved.

 描述（由适用提供）：肺癌目前是死亡​​率的主要原因。这些严重的神经毒性副作用之一在接受化学治疗剂的肺癌患者中发展为化学疗法诱导的周围神经病（CIPN）。我们的建议将集中在顺铂和紫杉醇引起的CIPN上，因为这是治疗普通癌症（包括非小细胞肺癌）的两种最有效，最广泛使用的化学疗法药物。 CIPN可能是化学疗法的剂量限制因素，也可以导致治疗过早终止，从而影响生存和生活质量。当前，尚无有效的疗法来处理基本的致病机制，例如神经变性。此外，当前处理CIPN疼痛症状的症状疗法通常无效。因此，在本应用中，替代形式的治疗形式是一种至关重要的医学，我们将重点介绍烟碱乙酰胆碱受体（NACHRS）调节剂，尤其是α7亚型，是CIP​​N治疗的潜在靶标。这些受体由参与疼痛传播的中枢和周围神经元细胞（背根神经节）以及巨噬细胞和其他参与炎症反应的细胞表达。在AIM 1中，我们将测试α7NACHR无声激动剂预防或改善顺铂和紫杉醇引起的周围神经病的发展，包括参与CIPN的明确定义的神经病理学。在AIM 2中，我们将在非小细胞肺癌细胞系和患者培养的患者衍生的肿瘤细胞以及伴有小鼠的肿瘤细胞中测试α7NACHR沉默激动剂，以消除这些药物刺激肿瘤生长或损害化学疗法的效力（顺铂和Paclitaxel）的可能性。 α7NACHR无声激动剂的CIPN将在轴承小鼠的肿瘤中得到证实。如果可以确定有效的治疗/预防，应该可以治疗患者或长时间的时间，因为剂量依赖性神经病将不会是有限的毒性和依从性，而生活质量将得到改善。