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

• 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
• 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

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.

项目摘要 随着新型早期诊断和新疗法的出现，癌症的存活率正在急剧上升。 但是，化学疗法患者经历的急性和慢性疼痛的形式很大 成功治疗后的多年之后和多年。随着化学疗法的流行 靶向和破坏癌细胞的身体，它们严重损害了其他器官，包括神经，导致 称为化学疗法诱导的周围神经病（CIPN）的疾病。症状通常会出现几分钟 治疗后的几个小时，包括手臂和手中的疼痛，燃烧或刺痛，触摸失去感觉， 执行常见的例程，绞痛，便秘，肌肉无力和平衡问题的困难。 寻找CIPN治疗是当前肿瘤学实践中的主要挑战之一， 识别新代理以预防和/或治疗CIPN是重中之重和长期目标。 不幸的是，目前尚无方法来评估CIPN或预测结果的程度。鉴别 疼痛CIPN表现的特定生物学机制需要一种诊断工具才能 监测活生生中的CIPN，以识别潜在的治疗靶点。有人提出有害 被称为活性氧和氮种（ROS/RN）的自由基会导致神经组织损伤并发挥关键 在神经退行性疾病中的作用。为了在活动物中测试这种机制，我们建议研究 在CIPN动物模型中，ROS对化学疗法反应的空间，时间和介入方面和 将体内成像结果与疾病进展相关。我们将专注于 与ROS的爆发有关，以及由所提出的选定所评估的神经组织中的重复损伤 慢性CIPN的标记。在目标1中，我们将首先证明ROS通路的重复刺激 小鼠导致与CIPN相关的症状。建立了此链接后，将在AIM 2中证明 其他化学疗法药物，例如紫杉醇和硼替佐米，它们具有不同的细胞毒性机制，但 显示相似的CIPN行为遵循相同的机械途径。最后，在AIM 3中，我们将检验我们的假设 通过证明药理学的合成和患者衍生的异种移植乳腺癌模型 使用FDA批准的药物的干预将使ROS和慢性CIPN最小化，而不会降低治疗 功效。这种组合成像，组织学，生化和行为方法的策略将导致 鉴定活动物中慢性疼痛的分子根，提供机械洞察力 CIPN的发病机理。总体而言，大纲提案将使我们能够将急性形式与慢性CIPN相关联 并探索几种图像引导的策略，以最大程度地减少CIPN。