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  • Disulfiram as a Cytotoxic Agent and Radiosensitizer Against Medulloblastoma

    Final Number:
    929

    Authors:
    Riccardo Serra MD; Joshua Casaos BS; Noah L Gorelick MD; Sakibul Huk; Arba Cecia; Henry Brem MD; Betty Tyler BA

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2018 Annual Meeting

    Introduction: Medulloblastoma, the most common pediatric brain tumor, is classified into 4 molecular subgroups: WNT, SHH, Group 3 and Group 4 (1). SHH tumors constitute 30% of all medulloblastomas, with TP53 mutation significantly worsening survival. Group 3 is particularly aggressive as a consequence of its tendency to metastasize. Disulfiram (DSF), a drug developed for chronic alcoholism, has been shown to be highly cytotoxic against many tumors, especially when combined with copper (Cu) (2).

    Methods: Medulloblastoma cell lines, ONS-76 (SHH Group, TP53 wild-type), UW228 (SHH Group, TP53 mutated) and D425med (Group 3), were treated with increasing concentrations of DSF as monotherapy and in combination with Cu. Analyses included CCK8 cytotoxicity, proliferation (using DSF at 100nM and DSF+Cu at 80nM), and clonogenic assays (100nM DSF and DSF+Cu). UW228 cells were exposed to DSF alone, DSF+Cu, or in combination with radiation (at doses of 0.5, 1 or 2 Gy). Nu/Nu mice with intracranial D425med were treated with oral DSF (100mg/kg) and oral Cu (2mg/kg). Results were analyzed with GraphPad Prism® and ImageJ.

    Results: The IC50 for DSF was 500nM at 48 hours, while the IC50 for DCF+Cu was < 300nM for all lines (p<0.001). DSF significantly decreased cell proliferation at a dose of 100nM, and combination therapy at 80nM (p<0.001). Clonogenic assays showed a synergistic reduction in colony formation in all samples with DSF+XRT and DSF+ Cu+XRT (p=0.0002). The in vivo experiment confirmed safety and tolerability of our proposed treatment, and an increase in median survival was observed in the group treated with DSF+Cu.

    Conclusions: DSF and Cu, two orally bioavailable compounds, exhibited remarkable efficacy and safety against medulloblastoma both in vitro and in vivo. Studies are under way to assess DSF’s role as a monotherapy and radiosensitizer, possibly paving the way for future clinical applications in medulloblastoma treatment.

    Patient Care: Disulfiram and copper, two safe and easily available compounds, showed a significant cytotoxic activity against a number of medulloblastoma cell lines. Their positive integration with radiation therapy paved the way for future uses in clinical settings, also considering their limited cost and the profound effects showed against the most aggressive subgroups of medulloblastoma.

    Learning Objectives: By the conclusion of this session, participants should be able to:1)understand the importance of repurposed drugs and of the combination of DSF-Cu, 2) Discuss the future implications of the data presented in this abstract, 3) Identify an effective combination of DSF-Cu and current strategies used for the treatment of medulloblastoma.

    References: (1) Taylor MD. et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol., 123:465–472 (2012). (2) Skrott, Z. et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552, 194–199 (2017).

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