Abstract LB-264: Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4

Abstract

Abstract Cancer incidence is rising and this global challenge is further exacerbated by resistance of advanced tumors to standard-of-care and emerging precision medicines. A promising approach to such unmet need for innovative and cost-effective cancer treatments is drug repurposing, exploitation of drugs already approved for other indications that show anticancer activity. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug that kills a broad range of cancer types in preclinical studies. Our nationwide population study reveals that patients who continued using disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. More importantly, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, present methods to detect its preferential accumulation in tumors and candidate biomarkers of impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-thought molecular target: NPL4 adapter of the p97/VCP segregase essential for protein recycling involved in multiple stress-response cellular pathways. Citation Format: Martin Mistrik, Zdenek Skrott, Marian Hajduch, Søren Friis, Petr Dzubak, Jan Gursky, Dusana Majera, Tomas Ozdian, Jana Vaclavkova, Martina Michalova, Pavla Pouckova, Boris Cvek, Klaus Kaae Andersen, Jiři Bartek. Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-264.