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

 描述(申请人提供)：超过80%的晚期胰腺癌患者报告体重减轻。肌肉的丧失在体重减轻中占了不成比例的比例，并产生了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，生存期缩短。事实上，这种体重/肌肉减少是一些癌症患者尸检时死亡的主要原因。这项提议开始挖掘这种观察的治疗潜力。我们假设，泛素-蛋白酶体途径的抑制剂和自噬的抑制剂--癌症中两种主要的肌肉降解途径--双硫兰(Antabuse)可以增加肌肉或稳定肌肉的损失，并可以改善肌肉功能。这一假说得到了我们团队和其他人的以下初步数据的支持：1)双硫兰可以改善动物模型中的肌肉丢失；2)抑制蛋白酶体似乎可以导致晚期癌症患者体重增加或体重稳定(我们的初步数据)。在这项提案的目标1中，我们将在晚期胰腺癌患者中进行I期剂量递增试验，使用双硫兰(将递增剂量)和化疗药物吉西他滨(剂量固定)，以得出安全的组合。我们将依靠患者报告的不良事件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，我们试图第一次证明双硫兰联合化疗对肌肉有有益的作用。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的剂量组合，并将连续检查1)肌肉活检，以显示双硫仑正击中预期的肌肉靶点，并寻找新的途径来更好地了解肌肉病理生物学；2)通过计算机断层扫描(主要终点)L3水平的肌肉区域；以及3)拳头握力。这项提议将是第一次测试双硫兰--一种具有90多年临床记录和治疗肌肉损失的基于机制的理论基础的药物--以评估其对肌肉的影响。这项建议承诺改善胰腺癌患者的生活质量，并为未来研究的改善奠定基础。 生死存亡。

 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.