AN IMAGING-BASED APPROACH TO UNDERSTAND AND PREDICT CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY

基于成像的方法来理解和预测化疗引起的周围神经病变

基本信息

批准号：
9981988
负责人：
Mikhail Y. Berezin
金额：
$ 12.52万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981988
关键词：
Acute Acute Pain Aftercare Animal Behavior Animal Model Animals Automobile Driving Axon Behavior Behavioral Biochemical Biochemical Reaction Biological Bortezomib Breast Cancer Model Cancer Model Cancer Patient Chemotherapy-induced peripheral neuropathy Chronic Chronic Phase Constipation Contrast Media DNA Deglutition Demyelinations Development Diagnostic Disease Progression Distal Dose Drug Formulations Electrophysiology (science)Equilibrium FDA approved Fluorescence Fluorescent Probes Frustration Functional disorder Goals Hand Histologic Hour Hypersensitivity Image Inflammatory Inflammatory Response Injury Intervention Link Measures Methods Mitochondria Molecular Molecular Probes Monitor Mus Muscle Cramp Muscle Weakness Myelin Nerve Nerve Tissue Neurodegenerative Disorders Neurologic Symptoms Neuropathy New Agents Nitrogen Numbness Optics Organ Oxidative Stress Oxygen Paclitaxel Pain Pathogenesis Pathway interactions Patient-derived xenograft models of breast cancer Patients Peripheral Nerves Pharmaceutical Preparations Pharmacology Phase Physicians Placebos Plant Roots Play Prevention trial Proteins Quality of life Rattus Risk Role Sensory Severities Signal Transduction Skin Specificity Stimulus Survival Rate Symptoms Testing Time Touch sensation Toxic effect Travel Treatment Efficacy Up-Regulation acute symptom arm associated symptom behavioral outcome cancer cell cancer survival cancer therapy chemotherapeutic agent chemotherapy chronic pain clinical translation clinically relevant cost cytokine cytotoxic density effective therapy experience image guided imaging approach imaging modality in vivo in vivo imaging insight mitochondrial dysfunction myelination neurotoxicity novel oncology outcome prediction oxaliplatin oxidation pain symptom peroxidation prevent response side effect therapeutic target tool tumor uptake

项目摘要

PROJECT SUMMARY Cancer survival rates are increasing dramatically as novel early diagnostics and new treatments emerge. However, there is a great cost in the form of acute and chronic pain that chemotherapy patients experience immediately after and for many years following successful treatment. As chemotherapy drugs travel throughout the body to target and destroy cancer cells, they severely damage other organs, including nerves, leading to a condition known as chemotherapy-induced peripheral neuropathy (CIPN). Symptoms often appear minutes to hours after the treatment and include pain in the arms and hands, burning or tingling, loss of sensation to touch, difficulties in performing common routines, cramping, constipation, muscle weakness, and balance problems. The search for a treatment for CIPN is one of the major challenges in current oncology practice, with the identification of new agents to prevent and/or treat CIPN being a top priority and long-term objective. Unfortunately, no methods are currently available to assess the extent of CIPN or predict outcomes. Identification of specific biological mechanisms underlying the manifestation of painful CIPN requires a diagnostic tool to monitor CIPN in living subjects to identify a potential therapeutic target. It has been proposed that damaging radicals known as reactive oxygen and nitrogen species (ROS/RNS) cause nerve tissue injury and play a critical role in neurodegenerative diseases. To test this mechanism in living animals, we propose to investigate the spatial, temporal, and interventional aspects of the ROS response to chemotherapy in CIPN animal models and correlate the in vivo imaging results with disease progression. We will be focusing on the mechanism that is related to the burst of ROS, and the repetitive damage in the nerve tissue assessed by the proposed selected markers of chronic CIPN. In the Aim 1 we will first demonstrate that the repetitive stimulation of ROS pathway in mice leads to the symptoms associated with CIPN. After establishing this link, will demonstrate in Aim 2 that the other chemotherapy drugs such as paclitaxel and bortezomib that act with different cytotoxic mechanisms but show similar CIPN behavior follow the same mechanistic pathway. Finally, in Aim 3 we will test our hypothesis in syngeneic and patient-derived xenograft breast cancer models by demonstrating that pharmacological intervention using FDA-approved drugs will minimize ROS and chronic CIPN while not undercutting treatment efficacy. This strategy of combined imaging, histological, biochemical and behavioral methods will lead to identification of the molecular roots of chronic pain in living animals, providing mechanistic insight into the pathogenesis of CIPN. Overall, the outline proposal will enable us to correlate the acute form with chronic CIPN and explore several image-guided strategies to minimize CIPN.

项目概要随着新的早期诊断和新治疗方法的出现，癌症存活率正在急剧增加。然而，化疗患者经历的急性和慢性疼痛会带来巨大的代价成功治疗后立即以及成功治疗后多年。随着化疗药物遍及全身身体瞄准并摧毁癌细胞，它们严重损害其他器官，包括神经，导致这种情况被称为化疗引起的周围神经病变（CIPN）。症状通常在几分钟内出现治疗后数小时，包括手臂和手部疼痛、烧灼感或刺痛、触觉丧失、执行日常活动有困难、痉挛、便秘、肌肉无力和平衡问题。寻找 CIPN 的治疗方法是当前肿瘤学实践中的主要挑战之一，确定预防和/或治疗 CIPN 的新药物是首要任务和长期目标。不幸的是，目前没有方法可以评估 CIPN 的程度或预测结果。鉴别疼痛 CIPN 表现背后的特定生物学机制需要一种诊断工具来监测活体受试者的 CIPN，以确定潜在的治疗靶点。有人提出，损害被称为活性氧和氮 (ROS/RNS) 的自由基会导致神经组织损伤，并在神经组织中发挥关键作用。在神经退行性疾病中的作用。为了在活体动物中测试这种机制，我们建议研究 CIPN 动物模型中 ROS 对化疗反应的空间、时间和介入方面将体内成像结果与疾病进展相关联。我们将重点关注的机制是与ROS的爆发有关，以及由建议选择的神经组织评估的重复性损伤慢性 CIPN 的标志物。在目标 1 中，我们将首先证明 ROS 通路的重复刺激小鼠会导致与 CIPN 相关的症状。建立此链接后，将在目标 2 中证明其他化疗药物，如紫杉醇和硼替佐米，具有不同的细胞毒性机制，但显示相似的 CIPN 行为遵循相同的机制路径。最后，在目标 3 中我们将检验我们的假设通过证明药理学，在同基因和患者来源的异种移植乳腺癌模型中使用 FDA 批准的药物进行干预将最大限度地减少 ROS 和慢性 CIPN，同时不会削弱治疗效果功效。这种结合成像、组织学、生化和行为方法的策略将导致识别活体动物慢性疼痛的分子根源，提供对疼痛机制的深入了解 CIPN 的发病机制。总体而言，大纲提案将使我们能够将急性形式与慢性 CIPN 联系起来并探索几种图像引导策略来最大限度地减少 CIPN。