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

• 批准号: 9131684
• 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
• 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/9131684
• 关键词: Accounting; 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; 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; Supportive care; System; Testing; Therapeutic; 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; skeletal; spine bone structure

 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（由申请人提供）：超过 80% 的晚期胰腺癌患者报告体重减轻。肌肉损失在体重减轻中所占比例不成比例，并产生巨大的发病率和死亡率：虚弱程度恶化、化疗难治性疾病、化疗毒性增加和生存期缩短。事实上，这种体重/肌肉损失是一些癌症患者尸检时死亡的主要原因。该提议开始利用此类观察的治疗潜力。我们假设双硫仑（Antabuse）是泛素蛋白酶体途径的抑制剂和自噬抑制剂（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。我们小组和其他人提供的以下初步数据支持了这一假设：1）双硫仑可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体重增加或体重稳定（我们的初步数据）。在该提案的目标#1中，我们将在晚期胰腺癌患者中进行I期剂量递增试验，使用双硫仑（剂量递增）加化疗药物吉西他滨（剂量固定）以获得安全的组合。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。在目标#2中，我们试图首次证明双硫仑联合化疗对肌肉有有益作用。我们将在一项随机、双盲、安慰剂对照试验的背景下，在 50 名胰腺癌患者中测试双硫仑和吉西他滨（来自目标 1）的剂量组合，并将连续检查 1) 肌肉活检，以显示双硫仑正在达到其预期的肌肉目标，并确定新的途径，以更好地了解肌肉病理学； 2) 通过计算机断层扫描扫描 L3 水平的肌肉面积（主要终点）； 3）握拳力量。该提案将是第一个测试双硫仑（一种具有 90 多年临床记录和基于机制的治疗肌肉损失的药物）的药物，以评估其对肌肉的影响。该提案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，以改善胰腺癌患者的生活质量。 生存。