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

项目摘要 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形式是巨大的成本 在成功治疗后的几年里，随着化疗药物在整个 当癌细胞被人体靶向并摧毁时，它们会严重损害其他器官，包括神经， 化疗引起的周围神经病变（chemotherapy induced peripheral neuropathy，CIPN）症状往往出现分钟， 治疗后数小时，包括手臂和手部疼痛，烧灼感或刺痛感，触觉丧失， 执行常规程序的困难，抽筋，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， 鉴定预防和/或治疗CIPN的新试剂是最优先和长期目标。 不幸的是，目前没有方法可以评估CIPN的程度或预测结果。识别 疼痛性CIPN表现背后的特定生物学机制需要一种诊断工具， 监测活体受试者的CIPN以确定潜在的治疗靶点。有人提出， 被称为活性氧和氮物质（ROS/RNS）的自由基引起神经组织损伤，并在神经元损伤中起关键作用。 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、时间和干预方面， 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， 与ROS的爆发有关，以及通过所提出的选择的评估神经组织中的重复性损伤。 慢性CIPN的标志物。在目的1中，我们将首先证明， 小鼠导致与CIPN相关的症状。建立这种联系后，将在目标2中证明， 其它化疗药物如紫杉醇和硼替佐米，它们以不同的细胞毒性机制起作用， 表现出相似的CIPN行为，遵循相同的机理途径。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 功效这种结合成像、组织学、生物化学和行为学方法的策略将导致 在活体动物中识别慢性疼痛的分子根源，提供对 CIPN的发病机制。总的来说，纲要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策略，以尽量减少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.