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

基于成像的方法来理解和预测化疗引起的周围神经病变

基本信息

批准号：
9751226
负责人：
Mikhail Y. Berezin
金额：
$ 37.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751226
关键词：
Acute Acute Pain Aftercare Animal Behavior Animal Model Animals Automobile Driving Axon Behavior Behavioral Biochemical Biochemical Reaction Biological Bortezomib Breast Cancer Model Cancer Model Cancer Patient Chemotherapy-induced peripheral neuropathy Chronic Chronic Phase Constipation Contrast Media DNA Deglutition Demyelinations Development Diagnostic Disease Progression Distal Dose Drug Formulations Electrophysiology (science)Equilibrium FDA approved Fluorescence Fluorescent Probes Frustration Functional disorder Goals Hand Histologic Hour Hypersensitivity Image Inflammatory Inflammatory Response Injury Intervention Link Measures Methods Mitochondria Molecular Molecular Probes Monitor Mus Muscle Cramp Muscle Weakness Myelin Nerve Nerve Tissue Neurodegenerative Disorders Neurologic Symptoms Neuropathy New Agents Nitrogen Numbness Optics Organ Oxidative Stress Oxygen Paclitaxel Pain Pathogenesis Pathway interactions Patient-derived xenograft models of breast cancer Patients Peripheral Nerves Pharmaceutical Preparations Pharmacology Phase Physicians Placebos Plant Roots Play Prevention trial Proteins Quality of life Rattus Risk Role Sensory Severities Signal Transduction Skin Specificity Stimulus Survival Rate Symptoms Testing Time Touch sensation Toxic effect Travel Treatment Efficacy Up-Regulation acute symptom arm associated symptom behavioral outcome cancer cell cancer survival cancer therapy chemotherapeutic agent chemotherapy chronic pain clinical translation clinically relevant cost cytokine cytotoxic density effective therapy experience image guided imaging approach imaging modality in vivo in vivo imaging insight mitochondrial dysfunction myelination neurotoxicity novel oncology outcome prediction oxaliplatin oxidation pain symptom peroxidation prevent response side effect therapeutic target tool tumor uptake

项目摘要

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.

项目总结