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.
Over 80% of advanced pancreas cancer patients suffer weight loss, which is primarily derived from muscle loss. This muscle loss spawns tremendous morbidity and mortality. Disulfiran (Antabuse) may augment muscle or stabilize its loss by inhibiting 2 major muscle loss pathways. We propose to test whether disulfiram plus chemotherapy can treat this muscle loss, improve quality of life, and, one day, lead to improved survival.
| Childs, Daniel S; Looker, Sherry; Le-Rademacher, Jennifer et al. (2018) What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study. Support Care Cancer : |
| Childs, Daniel S; Jatoi, Aminah (2018) A hunger for hunger: a review of palliative therapies for cancerassociated anorexia. Ann Palliat Med : |
| Le-Rademacher, Jennifer G; Crawford, Jeffrey; Evans, William J et al. (2017) Overcoming obstacles in the design of cancer anorexia/weight loss trials. Crit Rev Oncol Hematol 117:30-37 |
| Yusuf, Naima; Jatoi, Aminah (2017) Cancer-associated weight loss: releasing its firm grip on negative clinical outcomes. Curr Opin Support Palliat Care 11:259-260 |
