Abstract 3914: Repurposing disulfiram for use as an anticancer drug: a story about metabolism and metal binding

Disulfiram (DSF) is an FDA approved agent for the treatment of alcoholism with over 60 years of clinical use. It was identified in several high-throughput screen to be effective against glioma tumor initiating cells; this activity is amplified more than 100-fold in the presence of copper (Cu2+). DSF is metabolized to diethyldithiocarbamate (DDC), an established copper chelating agent. One mechanism attributed to the copper DDC (Cu(DDC)2) complex is proteosome inhibition. Cu(DDC)2 is very poorly soluble in aqueous solution; making it difficult to purse development for any cancer indication. A novel liposomal formulation of Cu(DDC)2 is described here; which represents the first iv injectable Cu(DDC)2. 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio) liposomes were prepared by extrusion methods in the presence of 300 mM unbuffered CuSO4 to ∼100 nm in size. DDC was added to these pre-formed liposomes at room temperature, unentrapped drug was removed using column chromatography. The therapeutic activity of this formulation was determined in vitro against a variety of cancer cell lines. The toxicity and pharmacokinetic (PK) behaviour of this formulation was determined in CD-1 mice. DDC was tested in the presence and absence of Cu2+ in vitro with U251, U87, MDA231-BR and A549 cell lines giving IC50 values greater than >10 μM in the absence and from 300- 900 nM in the presence of Cu2+. The liposomal Cu(DDC)2 formulation was as active as unencapsulated Cu(DDC)2 when tested in vitro. The maximum tolerated dose of liposomal Cu(DDC)2 was determined to be 8mg/kg given iv using a Q2D schedule for two weeks. The PK studies suggested that Cu(DDC)2 was rapidly released from circulating liposomes. Initial efficacy studies were completed using convection enhanced delivery of liposomal Cu(DDC)2 in the F98 rat glioma model. Treatment resulted in a statistically significant delay in tumour growth upon injection of 10 μL of 0.5 mg Cu(DDC)2 /mL solution. Further anti-tumor efficacy studies are being conducted in a subcutaneous leukemia xenograft model (MV-4-11). This work describes a novel formulation of Cu(DDC)2, the active agent generated when administering DSF and Cu to treat cancer. Citation Format: Moe Wehbe, Malathi Anantha, Ian Backstrom, Ada Leung, Kent Chen, Minghan Shi, Armaan Malhotra, Katarina Edwards, Leon Sanche, Marcel B. Bally. Repurposing disulfiram for use as an anticancer drug: a story about metabolism and metal binding. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3914.