Repurposing Disulfiram: A Novel Strategy to Help Cancer Patients Regain Muscle

重新利用双硫仑：帮助癌症患者恢复肌肉的新策略

基本信息

批准号：
9333283
负责人：
Martin Ernesto Fernandez-Zapico
金额：
$ 46.65万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333283
关键词：
Advanced Malignant Neoplasm Adverse effects Adverse event Amino Acids Animal Model Antineoplastic Agents Area Autophagocytosis Autopsy Biopsy Body Weight decreased Cancer Patient Cause of Death Cessation of life Clinical Data Degradation Pathway Disseminated Malignant Neoplasm Disulfiram Dose Eastern Cooperative Oncology Group Emaciation Equilibrium Future Hand Strength Health Personnel Homeostasis Intervention Investigation Lead Life Malignant Neoplasms Malignant neoplasm of pancreas Measurement Methodology Molecular Monitor Morbidity - disease rate Muscle Muscle function Muscular Atrophy Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Physicians Placebos Play Prospective Studies Proteasome Inhibition Proteins Quality of life Randomized Refractory Disease Reporting Role Scanning Skeletal Muscle Suggestion Supportive care System Testing Therapeutic Thinness Time Tissues Toxic effect Toxicity due to chemotherapy Ubiquitin Weight Weight Gain X-Ray Computed Tomography animal data base cancer cachexia cancer care cancer diagnosis chemotherapy double-blind placebo controlled trial gemcitabine grasp improved inhibitor/antagonist mortality multicatalytic endopeptidase complex novel strategies novel therapeutics oncology pre-clinical public health relevance spine bone structure

项目摘要

DESCRIPTION (provided by applicant): Over 80% of advanced pancreas cancer patients report weight loss. Loss of muscle accounts for a disproportionate degree of this weight loss and spawns tremendous morbidity and mortality: worsening debility, chemotherapy-refractory disease, heightened chemotherapy toxicity, and shortened survival. Indeed, this weight/muscle loss is the primary cause of death at autopsy in some cancer patients. This proposal begins to exploit the therapeutic potential of such observations. We hypothesize that disulfiram (Antabuse), an inhibitor of the ubiquitin-proteasome pathway and an inhibitor of autophagy -- the two main muscle degradative pathways in cancer -- can augment muscle or stabilize its loss and can improve muscle function. This hypothesis is bolstered by the following preliminary data from our group and from others: 1) disulfiram ameliorates muscle loss in an animal model; and 2) proteasome inhibition appears to lead to weight gain or weight stability in advanced cancer patients (our preliminary data). In aim #1 of this proposal, we will conduct a phase I dose-escalation trial in advanced pancreas cancer patients with disulfiram (to be dose-escalated) plus the chemotherapy agent gemcitabine (dose-fixed) to derive a safe combination. We will rely on both patient-reported and healthcare provider-reported adverse events to monitor toxicity and to derive a safe dose combination. In aim #2, we seek to demonstrate for the first time that disulfiram with chemotherapy has salutary effects on muscle. We will test the dose combination of disulfiram and gemcitabine (from aim #1) in 50 pancreas cancer patients in the context of a randomized, double-blind, placebo-controlled trial and will serially examine 1) muscle biopsies to show disulfiram is hitting its intended muscle targets and to identify new pathways to better understand muscle pathobiology; 2) muscle area at the L3 level with computerized tomography scans (primary endpoint); and 3) fist-grip strength. This proposal would be the first to test disulfiram -- an agent with a 90+ year clinical track record and a mechanism-based rationale for treating muscle loss -- to assess its impact on muscle. This proposal promises to improve quality of life in pancreas cancer patients and to lay the groundwork for future studies to improve survival.

描述（由适用提供）：超过80％的晚期胰腺癌患者报告体重减轻。失去肌肉的体重减轻程度不成比例，并产生了巨大的发病率和死亡率：令人担忧的耐用性，化学疗法 - 难治性疾病，化学疗法毒性的提高以及缩短的生存率。确实，这种体重/肌肉损失是一些癌症患者尸检的主要原因。该建议开始利用此类观察的治疗潜力。我们假设二硫酸（Antabuse）是泛素 - 蛋白酶体途径的抑制剂和自噬的抑制剂 - 癌症中的两种主要肌肉降解途径 - 可以增强肌肉或稳定其损失并可以改善肌肉功能。该假设得到了我们小组和其他人的以下初步数据的加强：1）二硫氨基二硫仑可以改善动物模型中的肌肉损失； 2）蛋白酶体抑制似乎会导致晚期癌症患者的体重增加或体重稳定性（我们的初步数据）。在该提案的AIM＃1中，我们将在晚期胰腺癌症患者（剂量降低）加上化学疗法吉西他滨（剂量固定）的晚期胰腺癌患者中进行I期剂量提升试验，以得出安全的组合。我们将依靠患者报告和医疗保健提供者报告的不良事件来监测毒性并得出安全的剂量组合。在AIM＃2中，我们试图首次证明对化学疗法的二硫次疗法对肌肉产生有益的影响。在一项随机的，双盲的，安慰剂对照试验的背景下，我们将测试50例胰腺癌患者的二硫仑和吉西他滨（来自AIM＃1）的剂量组合，并将串行检查1）肌肉活检以表明二硫次素的肌肉活检表明二硫次瘤正在打动其预期的肌肉靶标，并确定新的途径，以更好地了解肌肉毛皮学肌肉学的肌肉学； 2）在L3水平上进行计算机断层扫描的肌肉区域（主要终点）； 3）拳头强度。该提案将是第一个测试二硫兰氏菌的提案 - 一种临床记录90年以上的代理商，以及用于治疗肌肉损失的机制的基本原理 - 评估其对肌肉的影响。该建议有望改善胰腺癌患者的生活质量，并为未来的研究奠定基础。生存。