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：
8920522
负责人：
Robert Dantzer
金额：
$ 17.4万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920522
关键词：
Adhesives Afferent Neurons Animal Model Apoptotic Attention Axon Behavioral Assay Biological Brain Brain Injuries Cancer Patient Caring Cells Cerebrum Characteristics Chemotherapy-induced peripheral neuropathy Cisplatin Data Development Diabetic Neuropathies Discrimination Distress Dose Dose-Limiting Drug usage Excision FDA approved Functional disorder Hair Hand Health Hyperalgesia Immunohistochemistry In Vitro Incidence Interruption Ischemic Brain Injury Knowledge Lead Lipid Peroxidation MAPK8 gene 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 Structural defect Surface Swelling Symptoms TP53 gene Taxane Compound Testing Texture Therapeutic Toxic effect Work antitumor effect 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 relating to nervous system small molecule targeted treatment 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）：化学疗法诱导的周围神经病（CIPN）是降低剂量降低或治疗治疗的最常见原因的原因，该患者因癌症治疗的癌症（例如紫杉烷和基于铂的化合物）。 CIPN患者报告了外周感觉敏感性，刺痛感和疼痛的丧失，或者在“库存和手套”分布中丧失。由于蛋白酶体抑制剂和靶向疗法等较新的药物也经常导致CIPN，因此这种毒性的发生率预计会增加。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作用可能会影响生存。此外，周围神经病对生活质量有重大影响。没有FDA批准的CIPN治疗方法，而根本的机制才开始理解。啮齿动物研究暗示了CIPN的病理生理学中神经线粒体损伤。我们已经表明，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）在线粒体上特别保护脑神经元线粒体完整性，并减少iSchectic脑损伤模型中神经元丧失。在这里，我们建议将此知识应用于预防CIPN。我们的工作假设是，在周围神经元中线粒体上JNK激活或p53积累的局部靶向将阻止CIPN的发展。 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：研究有助于局部治疗的保护作用的细胞生物学机制。该研究应用具有创新性，因为：（a）尚未针对外周神经元中的线粒体p53/jnk途径来防止化学疗法诱导的神经元损伤和周围神经病；这个新颖的目标可能会为防止CIPN开辟新的治疗方法。（b）这项研究的成功完成不仅将开放新型的治疗选择，而且还提供了评估啮齿动物中感觉运动缺陷的行为测试。这些测试将允许回答一个问题是CIPN特征的疼痛和感觉运动缺陷的基础。（c）到目前为止，治疗CIPN的啮齿动物研究主要忽略了对癌症治疗的潜在干扰。我们计划使用p53阳性和阴性肿瘤分析药物治疗在体内的潜在干扰。该项目很重要，因为它可能会导致预防CIPN的新干预措施的发展，这仍然是治疗癌症患者的主要剂量限制毒性。线粒体损伤我可能还处于周围糖尿病神经病的起源，并导致其他形式的神经性疼痛，因此预期的发现也应使这群大量的患者受益。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

DOI：
10.1097/j.pain.0000000000000893
发表时间：
2017-06
期刊：
Pain
影响因子：
7.4
作者：
Krukowski K;Ma J;Golonzhka O;Laumet GO;Gutti T;van Duzer JH;Mazitschek R;Jarpe MB;Heijnen CJ;Kavelaars A
通讯作者：
Kavelaars A