Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial

Abstract

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

Repurposing Individualized Nutritional Intervention as a Therapeutic Component to Prevent the Adverse Effects of Radiotherapy in Patients With Cervical Cancer

“…The efficacy of a drug can be compromised by deterioration gastrointestinal absorption and therefore nutritional deterioration. The repurposing of drugs consists of finding new therapeutic indications for existing drugs, and therefore reducing the research times involved in the study of drugs with the advantage of knowing their risks already studied ( 70 , 71 ). For cervical cancer, the treatment is chemotherapy and radiotherapy, but both have adverse effects towards the maintenance of nutritional status, which increases morbidity and mortality and therefore the prognosis of the disease.…”

“…For cervical cancer, the treatment is chemotherapy and radiotherapy, but both have adverse effects towards the maintenance of nutritional status, which increases morbidity and mortality and therefore the prognosis of the disease. The nutritional intervention plus nutritional counseling should be reporpused as an essential part of the clinical trials for drug validation as it may improve benefits for patients with CC ( 71 ).…”

Novel Treatment Strategies for Glioblastoma

“…The inclusion of celecoxib as an adjuvant to therapeutics such as temozolomide, while showing good tolerability, was inconclusive in terms of providing a significant survival benefit [ 34 ]. Currently, the DIRECT phase II/III multicenter trial is examining the efficacy of disulfiram (potent inhibitor of aldehyde dehydrogenase) in a randomized controlled study with GBM patients, due for primary completion at the end of 2021 [ 35 ].…”

Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway

“…Last but not least, our present results are also highly relevant from the clinical point of view, not least because protein aggregation represents an unorthodox and so far largely unexplored mechanism of action for anticancer drugs. This rather unique mechanism may also contribute to the observed synergistic effects of DSF/copper with either ionizing radiation [44] or the DNA damage-inducing drug temozolomide [45] a combination currently tested in several clinical trials focusing on glioblastoma patients [46][47][48], as well as a combination of DSF with cisplatin [49]. We hope that the data we report here will inspire further research in this rapidly evolving area of biomedicine, and yield additional effective therapies based on combining DSF/copper (CuET) with other currently used DNA damage-related therapeutic modalities.…”