ASSESSMENT OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY WITH ACTIVABLE PROBES

使用可激活探针评估化疗引起的周围神经病变

• 批准号: 8958415
• 负责人: Mikhail Y. Berezin
• 金额: $ 16.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958415
• 关键词: Acute; Adverse effects; Affect; Aftercare; Animal Model; Animals; Biochemical Reaction; Biological Assay; Biological Markers; Bortezomib; Cancer Patient; Chemotherapy-induced peripheral neuropathy; Chronic; Clothing; Contrast Media; DNA; Data; Deglutition; Development; Diagnostic; Disease Progression; Distal; Dose; Drug Design; Drug Formulations; Evaluation; Fluorescence; Fluorescent Probes; Frustration; Goals; Hour; Hypersensitivity; Image; Imagery; Imaging Device; Intervention; Lead; Life; Measures; Methods; Mission; Molecular Target; Monitor; Muscle Cramp; Muscle Weakness; Myelin; National Cancer Institute; Nerve; Nerve Tissue; Neurologic; Neuropathy; New Agents; Optics; Outcome; Oxidative Stress; Paclitaxel; Pain; Pathogenesis; Patients; Peripheral Nerves; Pharmaceutical Preparations; Phase; Physicians; Placebos; Prevention trial; Proteins; Quality of life; Rattus; Reactive Oxygen Species; Reporting; Research Project Grants; Risk; Sensory; Signal Transduction; Specificity; Staging; Stimulus; Symptoms; System; Techniques; Time; Toxic effect; Vincristine; Work; base; behavioral outcome; cancer therapy; chemotherapeutic agent; chemotherapy; dosage; effective therapy; experience; grasp; image guided; improved; in vivo; insight; mitochondrial dysfunction; molecular imaging; nerve injury; neuroinflammation; neurotoxic; neurotoxicity; novel; oncology; overexpression; oxaliplatin; oxidation; oxidative damage; peroxidation; prevent; programs; public health relevance; response; tool

 DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling side effect of cancer treatment affecting peripheral nerve system of millions of cancer patients. The search for the treatment of 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 a long-term objective of this study. Unfortunately, no biomarkers are currently available to assess the extent of CIPN or to predict outcomes in CIPN even in animal models. Since oxidative stress in nerve is implicated as key mechanism in CIPN, the extent of CIPN can be identified non-invasively with fluorescent probes specific to reactive oxygen species (ROS) overexpressed in peripheral nerves. In this project, we develop a novel imaging approach for detecting chemotherapy-induced ROS in vivo in animal models. Our near infrared (NIR) ROS-sensitive probes report oxidative activity in nerves minutes after oxaliplatin treatment providing a window into acute stages of neuroinflammation in real time. We hypothesize that the detected burst of ROS in nerve tissue immediately following chemotherapy administration stimulates neuroinflammatory cascades resulting in long term neuropathy. Correspondingly, suppression of the ROS spikes at the time of treatment is expected to minimize neuroinflammation and neurological symptoms associated with CIPN. In the first aim, the fluorescence signal intensity from the probe in the nerve tissue will be correlated longitudinally with the dosing of oxaliplatin, expression of established immunohistochemical markers of oxidative stress and the behavioral outcome. We expect a positive correlation between the oxaliplatin dosage and fluorescence activation. In the second aim, we will be applying this imaging approach to investigate several interventional strategies with the goal to reduce early ROS response and minimize CIPN. Positive results will confirm that suppression of ROS in the acute phase stops the progression of CIPN. This first image-guided approach for measuring the effect of chemotherapy on CIPN in vivo using appropriate animal models will provide a tool to: 1) assess the neurotoxicity of the current and novel chemotherapeutic agents and develop new formulations with reduced CIPN, 2) instigate the discovery of drugs that, in combination with existing chemotherapy agents, will minimize neurotoxic adverse effects. Overall, this study will lead to significant progress in CIPN treatment and chemotherapy drug design to extend and improve the life of cancer patients.

 描述（由申请人提供）：化疗诱导的周围神经病变（CIPN）是癌症治疗的常见和潜在致残性副作用，影响数百万癌症患者的周围神经系统。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的新药是本研究的首要任务和长期目标。不幸的是，目前没有生物标志物可用于评估CIPN的程度或预测CIPN的结果，即使在动物模型中。由于神经中的氧化应激被认为是CIPN的关键机制，CIPN的程度可以用特异于外周神经中过表达的活性氧（ROS）的荧光探针非侵入性地鉴定。在这个项目中，我们开发了一种新的成像方法来检测化疗诱导的ROS在体内的动物模型。我们的近红外（NIR）ROS敏感探针报告了奥沙利铂治疗后几分钟神经中的氧化活性，为真实的神经炎症急性期提供了一个窗口。我们假设，检测到的ROS在神经组织中的爆发后立即化疗管理刺激神经炎症级联反应，导致长期神经病变。相应地，治疗时抑制活性氧峰值预计将最大限度地减少与CIPN相关的神经炎症和神经系统症状。在第一个目标中，来自神经组织中探针的荧光信号强度将与奥沙利铂的剂量、氧化应激的既定免疫组织化学标志物的表达和行为结果纵向相关。我们预期奥沙利铂剂量与荧光活化之间存在正相关性。在第二个目标中，我们将应用这种成像方法来研究几种干预策略，目的是减少早期ROS反应并最大限度地减少CIPN。阳性结果将证实在急性期抑制ROS可阻止CIPN的进展。这种使用适当的动物模型在体内测量化疗对CIPN的影响的第一种图像引导方法将提供一种工具：1）评估当前和新型化疗剂的神经毒性并开发具有降低的CIPN的新制剂，2）促使发现与现有化疗剂组合将使神经毒性副作用最小化的药物。总的来说，这项研究将导致CIPN治疗和化疗药物设计的重大进展，以延长和改善癌症患者的生命。