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Disulfiram as a Therapeutic Agent for Metastatic Malignant Melanoma-Old Myth or New Logos?
Francisco Meraz-Torres1, Sarah Plöger1, Claus Garbe1
1Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany.
Abstract:
New therapeutic concepts such as anti-PD-1-based immunotherapy or targeted therapy with BRAF and MEK inhibitors have significantly improved the survival of melanoma patients. However, about 20% of patients with targeted therapy and up to 50% with immunotherapies do not respond to their first-line treatment or rapidly develop resistance. In addition, there is no approved targeted therapy for certain subgroups, namely BRAF wild-type melanomas, although they often bear aggressive tumor biology. A repurposing of already approved drugs is a promising strategy to fill this gap, as it will result in comparatively low costs, lower risks and time savings. Disulfiram (DSF), the first drug to treat alcoholism, which received approval from the US Food and Drug Administration more than 60 years ago, is such a drug candidate. There is growing evidence that DSF has great potential for the treatment of various human cancers, including melanoma. Several mechanisms of its antitumor activity have been identified, amongst them the inhibition of the ubiquitin-proteasome system, the induction of reactive oxygen species and various death signaling pathways. This article provides an overview of the application of DSF in humans, its molecular mechanisms and targets in cancer therapy with a focus on melanoma. The results of clinical studies and experimental combination approaches of DSF with various cancer therapies are discussed, with the aim of exploring the potential of DSF in melanoma therapy.
Insights
Disulfiram (DSF), an alcoholism drug, shows promise for melanoma treatment. It offers a cost-effective strategy for patients resistant to current therapies, including those with BRAF wild-type melanoma.
Area of Science:
- Oncology
- Drug Repurposing
- Melanoma Therapeutics
Background:
- Immunotherapy and targeted therapies (BRAF/MEK inhibitors) have improved melanoma survival.
- Significant patient populations exhibit primary resistance or develop acquired resistance to these treatments.
- BRAF wild-type melanomas lack approved targeted therapies despite aggressive biology.
Purpose of the Study:
- To review the potential of disulfiram (DSF) as a repurposed drug for melanoma treatment.
- To explore the molecular mechanisms and targets of DSF in cancer therapy, focusing on melanoma.
- To discuss clinical studies and combination approaches involving DSF in melanoma.
Main Methods:
- Literature review of disulfiram's application in human cancer therapy.
- Analysis of identified molecular mechanisms of DSF's antitumor activity.
- Evaluation of clinical trial data and preclinical combination studies of DSF in melanoma.
Main Results:
- Disulfiram (DSF) demonstrates antitumor activity through mechanisms including proteasome inhibition, reactive oxygen species induction, and activation of death signaling pathways.
- Growing evidence supports DSF's potential in treating various cancers, including melanoma.
- Clinical studies and combination approaches suggest DSF's therapeutic potential in melanoma.
Conclusions:
- Disulfiram (DSF) represents a promising repurposed drug candidate for melanoma, particularly for treatment-resistant or BRAF wild-type cases.
- DSF's established safety profile and low cost make it an attractive option for melanoma therapy.
- Further investigation into DSF's efficacy and combination strategies is warranted to optimize its role in melanoma treatment.
