ASSESSMENT OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY WITH ACTIVABLE PROBES

点击翻译按钮获取中文摘要

 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.