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：
10017018
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017018
关键词：
Advanced Malignant Neoplasm 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 Oncology Pathway interactions Patients Pharmaceutical Preparations Phase 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 advanced pancreatic cancer 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 pancreatic cancer patients phase I trial pre-clinical primary endpoint public health relevance side effect 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（由申请人提供）：超过 80% 的晚期胰腺癌患者报告体重减轻，其中肌肉损失的程度不成比例，并导致巨大的发病率和死亡率：衰弱恶化、化疗难治性疾病、大量化疗毒性和副作用。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。我们开始利用这种观察结果的治疗潜力。（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）可以增强或稳定其损失，并可以改善肌肉功能，以下初步结果支持了这一假设。我们小组和其他人的数据：1）双硫仑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）。该提案的目标#1，我们将在晚期胰腺癌患者中进行双硫仑（剂量递增）加化疗药物吉西他滨（剂量固定）的 I 期剂量递增试验，以得出我们将依赖的安全组合。根据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。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的剂量组合（来自目标 #1），并将连续检查 1) 肌肉活检，以显示双硫仑达到其预期效果肌肉目标并确定新的途径以更好地了解路径肌肉生物学；2）通过计算机断层扫描（主要终点）进行 L3 水平的肌肉区域；以及 3）握拳该提案将首次测试双硫仑（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），以评估其对肌肉的影响。该提案有望改善生活质量。胰腺癌患者，并为未来的研究奠定基础，以改善生存。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Weight loss over time and survival: a landmark analysis of 1000+ prospectively treated and monitored lung cancer patients.

随着时间的推移体重减轻和生存率：对 1000 名前瞻性治疗和监测的肺癌患者进行的具有里程碑意义的分析。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Le;Lopez, Camden;Wolfe, Eric;Foster, Nathan R;Mandrekar, Sumithra J;Wang, Xiaofei;Kumar, Rajiv;Adjei, Ale;Jatoi, Aminah
通讯作者：
Jatoi, Aminah

What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study.

什么%20发生在%20%20其他%2020%%20of%20癌症%20患者%20与%20化疗引起的%20恶心%20和%20呕吐%20（CINV）？%20A%20单一机构%20定性%20研究。

DOI：
发表时间：
2019-01
期刊：
影响因子：
0
作者：
Childs, Daniel S;Looker, Sherry;Le;Ridgeway, Jennifer L;Breitkopf, Carmen Radecki;Jatoi, Aminah
通讯作者：
Jatoi, Aminah

Does the Poly (ADP-Ribose) Polymerase Inhibitor Veliparib Merit Further Study for Cancer-Associated Weight Loss? Observations and Conclusions from Sixty Prospectively Treated Patients.

聚（ADP-核糖）聚合酶抑制剂 Veliparib 是否值得进一步研究癌症相关的减肥效果？

DOI：
发表时间：
2018
期刊：
影响因子：
2.8
作者：
Doles, Jason D;Hogan, Kelly A;O'Connor, Jennifer;Wahner Hendrickson, Andrea E;Huston, Olivia;Jatoi, Aminah
通讯作者：
Jatoi, Aminah

Editorial: Merging therapeutics and supportive care: synergy and yield.

社论：合并治疗和支持护理：协同作用和产量。