Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial

Mego, Michal; Světlovská, Daniela; Angelis, De; Kalavska, Katarína; Lesko, Peter; Makovnik, Marek; Obertová, Jana; Országhová, Zuzana; Palacka, Patrik; Rečková, Mária; Rejleková, Katarína; Syčová-Milá, Zuzana; Mardiak, Jozef; Chovanec, Michal

doi:10.1007/s10637-022-01271-1

Cited by 9 publications

(7 citation statements)

References 30 publications

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“…In a phase II trial of temozolomide + DSF/Cu for recurrent temozolomide-resistant glioblastoma, 14% of patients experienced a clinical benefit, with stable disease for over six months; this finding suggests that in a small subset of patients with glioblastoma, DSF/Cu may exhibit a modest positive effect [ 157 ]. A phase II trial of patients with multiple relapsed or refractory testicular germ cell tumor (GCT) found that no patients exhibited an objective response, leading to the study’s termination in its first stage [ 158 ].…”

Section: Resultsmentioning

confidence: 99%

Disulfiram: Mechanisms, Applications, and Challenges

et al. 2023

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Background: Since disulfiram’s discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were “disulfiram” and “Antabuse”. Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948–2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a “repurposed” agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.

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Section: Resultsmentioning

confidence: 99%

Disulfiram: Mechanisms, Applications, and Challenges

et al. 2023

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“…Despite the strong in vitro antineoplastic activities of copper ionophores, as well as their selectivity toward tumor cells (25,38), clinical trials using the copper ionophores elesclomol and disulfiram failed to produce significant benefits for cancer treatment (39)(40)(41)(42)(43)(44)(45). Drug delivery and limited bioavailability, along with the lack of robust biomarkers in these untargeted clinical trials, might be responsible for this relative failure.…”

Section: Discussionmentioning

confidence: 99%

SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia

Moison,

Gracias,

Schmitt

et al. 2024

Sci. Adv.

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In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1 -mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1 -mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1 -mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1 -mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore–based therapies.

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“…Except from the small study in non-small cell lung cancer, the positive laboratory findings have been difficult to translate to clinical benefit also for other cancers, with negative trials in patients with prostate cancer and in cisplatin-responsive malignant neoplasms. 21,40,42,43 JAMA Network Open | Oncology…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, from a toxicity point of view, a higher dose of disulfiram is not feasible. Except from the small study in non–small cell lung cancer, the positive laboratory findings have been difficult to translate to clinical benefit also for other cancers, with negative trials in patients with prostate cancer and in cisplatin-responsive malignant neoplasms …”

Section: Discussionmentioning

confidence: 99%

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

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Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial

Cited by 9 publications

References 30 publications

Disulfiram: Mechanisms, Applications, and Challenges

Disulfiram: Mechanisms, Applications, and Challenges

SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

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