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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.