Targeting Neural Mitochondria to Treat Chemotherapy-Induced Peripheral Neuropathy

靶向神经线粒体治疗化疗引起的周围神经病变

基本信息

批准号：
8771592
负责人：
Robert Dantzer
金额：
$ 20.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771592
关键词：
Adhesives Afferent Neurons Animal Model Apoptotic Attention Axon Behavioral Assay Biological Brain Brain Injuries Cancer Patient Caring Cells Cerebrum Characteristics Cisplatin Data Development Diabetic Neuropathies Discrimination Distress Dose Dose-Limiting Drug usage Excision FDA approved Functional disorder Hair Hand Hyperalgesia Immunohistochemistry In Vitro Incidence Interruption Ischemic Brain Injury Knowledge Lead Lipid Peroxidation Malignant Neoplasms Measurement Measures Mechanical Stimulation Mechanics Mission Mitochondria Modeling Molecular N-terminal National Cancer Institute Nerve Fibers Neurons Ovarian Carcinoma Oxidative Stress Paclitaxel Pain Pain Research Pathway interactions Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Preparations Phosphotransferases Platinum Prevention Preventive Intervention Production Proteasome Inhibitor Public Health Quality of life Reporting Research Research Support Respiration Risk Rodent Rodent Model Sensorimotor functions Sensory Specificity Spinal Ganglia Stress Surface Swelling Symptoms TP53 gene Taxane Compound Testing Texture Therapeutic Toxic effect Work base behavior test cancer therapy chemotherapeutic agent chemotherapy density foot high risk in vivo inhibitor/antagonist innovation insight mechanical allodynia mitochondrial dysfunction nerve supply neuron loss neuronal cell body new therapeutic target novel novel therapeutics painful neuropathy patient population pifithrin prevent protective effect public health relevance relating to nervous system small molecule stress-activated protein kinase 1 taxane tumor

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequent cause of dose reduction or treatment discontinuation in patients treated for cancer with commonly used drugs such as taxanes and platinum-based compounds. Patients with CIPN report loss of peripheral sensory sensitivity, tingling, and pain separately or in combination in a 'stocking and glove' distribution. The incidence of this toxicity is anticipated t increase as newer drugs like proteasome inhibitors and targeted therapies are also frequently leading to CIPN. Recent estimates indicate that several hundred thousand patients suffer from CIPN each year and the dose limiting effects of this toxicity are likely to impact survival. In addition, peripheral neuropathy has a major impact on quality of life. There are no FDA-approved treatments for CIPN and the underlying mechanisms are only begun to be understood. Rodent studies implicate neural mitochondrial damage in the pathophysiology of CIPN. We have shown that inhibition of the accumulation of the pro-apoptotic factor p53 or inhibition of activation of the stress kinase c-Jun N-terminal Kinase (JNK) specifically at the mitochondria protects cerebral neuronal mitochondrial integrity and reduces neuronal loss in a model of ischemic brain damage. Here we propose to apply this knowledge to the prevention of CIPN. Our working hypothesis is that local targeting of JNK activation or p53 accumulation at the mitochondria in peripheral neurons will prevent development of CIPN. To test our hypothesis we will pursue the following three specific aims: 1: Determine the effect of local targeting of mitochondrial JNK/P53 on paclitaxel-induced mechanical hyperalgesia and verify that it does not interfere with cancer therapy 2: Inhibit the JNK/p53 pathway to protect against sensorimotor dysfunction and loss of paw innervation; 3: Investigate the cell biological mechanisms contributing to the protective effects of local treatment. This research application is innovative because: (a) the mitochondrial P53/JNK pathway in peripheral neurons has not been targeted to protect against chemotherapy-induced neuronal damage and peripheral neuropathy; this novel target is likely to open up a new range of therapeutic means for preventing CIPN. (b) Successful completion of this study will not only open novel therapeutic options but also provide behavioral tests for assessing sensorimotor deficits in rodents. These tests will allow answering the question whether the same or distinct molecular mechanisms underlie pain and sensorimotor deficits that are characteristic of CIPN. (c) Until now, rodent studies treating CIPN mostly ignored potential interference with cancer therapy. We plan to analyze a potential interference of drug treatment in vivo as well as in vitro using p53 positive and negative tumors. This project is significant because it will likely lead to development of novel interventions for prevention of CIPN, still the major dose-limiting toxicity in patients treated for cancer. Mitochondrial damage i probably also at the origin of peripheral diabetic neuropathy and contributes to other forms of neuropathic pain, so the expected findings should benefit this large population of patients as well.

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）是使用紫杉烷类和铂类化合物等常用药物治疗癌症的患者减少剂量或停止治疗的最常见原因。 CIPN 患者报告外周感觉敏感性丧失、刺痛和疼痛单独或以“袜子和手套”分布组合出现。随着蛋白酶体抑制剂和靶向治疗等新药物也经常导致 CIPN，预计这种毒性的发生率将会增加。最近的估计表明，每年有数十万名患者患有 CIPN，这种毒性的剂量限制效应可能会影响生存。此外，周围神经病变对生活质量也有重大影响。目前还没有 FDA 批准的 CIPN 治疗方法，其潜在机制才刚刚开始被了解。啮齿动物研究表明 CIPN 的病理生理学涉及神经线粒体损伤。我们已经证明，在线粒体模型中，抑制促凋亡因子 p53 的积累或抑制应激激酶 c-Jun N 末端激酶 (JNK) 的激活，可以保护脑神经元线粒体完整性并减少神经元损失。缺血性脑损伤。在这里，我们建议将这些知识应用于 CIPN 的预防。我们的工作假设是，局部靶向 JNK 激活或 p53 在周围神经元线粒体处的积累将阻止 CIPN 的发展。为了检验我们的假设，我们将追求以下三个具体目标： 1：确定线粒体 JNK/P53 局部靶向对紫杉醇诱导的机械痛觉过敏的影响，并验证它不会干扰癌症治疗 2：抑制 JNK/p53 通路防止感觉运动功能障碍和爪子神经支配丧失； 3：研究有助于局部治疗保护作用的细胞生物学机制。这项研究应用具有创新性，因为：(a) 周围神经元中的线粒体 P53/JNK 通路尚未针对化疗引起的神经元损伤和周围神经病变进行保护；这一新靶点可能会开辟一系列预防 CIPN 的新治疗手段。 (b) 这项研究的成功完成不仅将开辟新的治疗选择，而且还将提供用于评估啮齿类动物感觉运动缺陷的行为测试。这些测试将能够回答以下问题：CIPN 特有的疼痛和感觉运动缺陷是否存在相同或不同的分子机制。 (c) 到目前为止，治疗 CIPN 的啮齿动物研究大多忽略了对癌症治疗的潜在干扰。我们计划使用 p53 阳性和阴性肿瘤来分析体内和体外药物治疗的潜在干扰。该项目意义重大，因为它可能会导致开发新的干预措施来预防 CIPN，CIPN 仍然是癌症治疗患者的主要剂量限制性毒性。线粒体损伤可能也是周围糖尿病神经病变的根源，并导致其他形式的神经性疼痛，因此预期的发现也应该使这一大批患者受益。