title: Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma.
abstract: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.
  
  
  
  To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.
  
  
  
  Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).
  
  
  
  DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 22(15); 3860-75. ©2016 AACR.
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J Connor
authors.initials: JC
authors.lastname: Wells
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Grinshtein
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: King
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Hao
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ngoc-Ha
authors.initials: NH
authors.lastname: Dang
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Wang
authors.affiliation: Drug Discovery Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.affiliation: Drug Discovery Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Uehling
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada. Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Easaw
authors.affiliation: Department of Cell Biology & Anatomy, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Artee
authors.initials: A
authors.lastname: Luchman
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. Department of Cell Biology & Anatomy, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Oncology, University of Calgary, Calgary, Alberta, Canada. senger@ucalgary.ca srobbins@ucalgary.ca.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Robbins
authors.affiliation: Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Oncology, University of Calgary, Calgary, Alberta, Canada. senger@ucalgary.ca srobbins@ucalgary.ca.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Senger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004221:Disulfiram / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003300:Copper; D003606:Dacarbazine; D046988:Proteasome Endopeptidase Complex; D004221:Disulfiram; D000077204:Temozolomide