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

项目总结 随着新的早期诊断和新的治疗方法的出现，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是有巨大代价的。 在成功治疗后立即发生，并持续多年。随着化疗药物在全国各地传播 体内靶向并摧毁癌细胞，它们会严重损害包括神经在内的其他器官，导致 这种情况被称为化疗引起的周围神经病变(CIPN)。症状通常出现在几分钟后 治疗后几个小时，包括手臂和手疼痛，灼热或刺痛，触觉丧失， 执行常规动作困难、抽筋、便秘、肌肉无力和平衡问题。 寻找治疗CIPN的方法是当前肿瘤学实践中的主要挑战之一， 寻找预防和/或治疗CIPN的新药物是一项重中之重和长期目标。 不幸的是，目前还没有方法可以评估CIPN的范围或预测结果。鉴定 疼痛CIPN表现的特定生物学机制的研究需要一种诊断工具 监测活体受试者的CIPN以确定潜在的治疗靶点。有人提出，具有破坏性的 被称为活性氧和氮物种(ROS/RNS)的自由基会导致神经组织损伤，并在 在神经退行性疾病中的作用。为了在活体动物身上测试这一机制，我们建议研究 CIPN动物模型中ROS对化疗反应的空间、时间和干预方面的研究 将体内成像结果与疾病进展相关联。我们将重点关注这一机制，即 与ROS的爆发有关，以及由建议的选定的评估神经组织的重复性损伤 慢性CIPN的标志物。在目标1中，我们将首先证明ROS通路的重复刺激在 小鼠导致与CIPN相关的症状。在建立这种联系之后，将在目标2中展示 其他化疗药物，如紫杉醇和波特佐米，具有不同的细胞毒性机制，但 表现出相似的CIPN行为遵循相同的机制途径。最后，在目标3中，我们将检验我们的假设 在同基因和患者来源的异种乳腺癌模型中通过证明药理作用 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，同时不会影响治疗 功效。这一结合成像、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 CIPN的发病机制。总体而言，大纲建议将使我们能够将急性肺炎与慢性CIPN联系起来 并探索几种图像引导策略，以最大限度地减少CIPN。

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.