Principal Investigator

Aminah
Jatoi
Awardee Organization

Mayo Clinic Rochester
United States

Fiscal Year
2020
Activity Code
R01
Project End Date

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

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.

Publications

  • Le-Rademacher JG, Crawford J, Evans WJ, Jatoi A. Overcoming obstacles in the design of cancer anorexia/weight loss trials. Critical reviews in oncology/hematology. 2017 Sep;117:30-37. Epub 2017 Jun 24. PMID: 28807233
  • Kunz HE, Port JD, Kaufman KR, Jatoi A, Hart CR, Gries KJ, Lanza IR, Kumar R. Skeletal muscle mitochondrial dysfunction and muscle and whole body functional deficits in cancer patients with weight loss. Journal of applied physiology (Bethesda, Md. : 1985). 2022 Feb 1;132(2):388-401. Epub 2021 Dec 23. PMID: 34941442
  • Childs DS, Looker S, Le-Rademacher J, Ridgeway JL, Breitkopf CR, Jatoi A. What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2019 Jan;27(1):249-255. Epub 2018 Jun 25. PMID: 29938306
  • Jatoi A, Laird BJA. Editorial: Merging therapeutics and supportive care: synergy and yield. Current opinion in supportive and palliative care. 2019 Dec;13(4):277-278. PMID: 31644452
  • Le-Rademacher J, Lopez C, Wolfe E, Foster NR, Mandrekar SJ, Wang X, Kumar R, Adjei A, Jatoi A. Weight loss over time and survival: a landmark analysis of 1000+ prospectively treated and monitored lung cancer patients. Journal of cachexia, sarcopenia and muscle. 2020 Dec;11(6):1501-1508. Epub 2020 Sep 17. PMID: 32940014
  • Childs DS, Yoon HH, Eiring RA, Jin Z, Jochum JA, Pitot HC, Jatoi A. Falls: descriptive rates and circumstances in age-unspecified patients with locally advanced esophageal cancer. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2021 Feb;29(2):733-739. Epub 2020 May 24. PMID: 32447502
  • Berent TE, Dorschner JM, Meyer T, Craig TA, Wang X, Kunz H, Jatoi A, Lanza IR, Chen H, Kumar R. Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice. PloS one. 2019 Dec 18;14(12):e0226440. doi: 10.1371/journal.pone.0226440. eCollection 2019. PMID: 31851697
  • Yusuf N, Jatoi A. Cancer-associated weight loss: releasing its firm grip on negative clinical outcomes. Current opinion in supportive and palliative care. 2017 Dec;11(4):259-260. PMID: 28914643
  • Doles JD, Hogan KA, O'Connor J, Wahner Hendrickson AE, Huston O, Jatoi A. Does the Poly (ADP-Ribose) Polymerase Inhibitor Veliparib Merit Further Study for Cancer-Associated Weight Loss? Observations and Conclusions from Sixty Prospectively Treated Patients. Journal of palliative medicine. 2018 Sep;21(9):1334-1338. Epub 2018 May 24. PMID: 29792535
  • Childs DS, Jatoi A. A hunger for hunger: a review of palliative therapies for cancer-associated anorexia. Annals of palliative medicine. 2019 Jan;8(1):50-58. Epub 2018 May 24. PMID: 29860861

Clinical Trials

Study Name Clinical Trial ID
Disulfiram and Chemotherapy in Treating Patients With Refractory Solid Tumors or Metastatic Pancreatic Cancer NCT02671890