ASSESSMENT OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY WITH ACTIVABLE PROBES

 描述(申请人提供)：化疗引起的周围神经病变(CIPN)是癌症治疗的一种常见且可能致残的副作用，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，寻找新的药物来预防和/或治疗CIPN是本研究的首要任务和长期目标。不幸的是，目前还没有生物标志物可用于评估CIPN的范围或预测CIPN的结果，即使在动物模型中也是如此。由于氧化应激参与了CIPN的发病机制，因此，针对周围神经中过度表达的活性氧物种(ROS)的荧光探针可以无创性地识别CIPN的程度。在本项目中，我们开发了一种新的成像方法，用于在动物模型中检测化疗诱导的体内ROS。我们的近红外(NIR)ROS敏感探针在奥沙利铂治疗几分钟后报告神经中的氧化活性，为实时了解神经炎症的急性阶段提供了窗口。我们假设，化疗后立即在神经组织中检测到的ROS爆发刺激了神经炎性级联反应，从而导致长期的神经病变。相应地，在治疗时抑制ROS峰有望将与CIPN相关的神经炎症和神经症状降至最低。在第一个目标中，探针在神经组织中的荧光信号强度将与奥沙利铂的剂量、氧化应激已建立的免疫组织化学标记物的表达以及行为结果纵向相关。我们期望奥沙利铂剂量与荧光激活呈正相关。在第二个目标中，我们将应用这种成像方法来研究几种介入策略，目的是减少早期ROS反应，最大限度地减少CIPN。阳性结果将证实，在急性期抑制ROS可以阻止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药物的神经毒性，并开发减少CIPN的新配方；2)促进发现与现有化疗药物相结合的药物，将神经毒性不良反应降至最低。总体而言，这项研究将在CIPN治疗和化疗药物设计方面取得重大进展，以延长和改善癌症患者的生命。

 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.