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Clin Cancer Res. 2018 Oct 15. pii: clincanres.1854.2018. doi: 10.1158/1078-0432.CCR-18-1854. [Epub ahead of print]

Ketoconazole and Posaconazole Selectively Target HK2 Expressing Glioblastoma Cells.

Author information

1
Children's Hospital, Department of Neurological Surgery, University of Pittsburgh.
2
MacFeeters Hamilton Center for Neuro-Oncology, University Health Network, University of Toronto.
3
Cancer research, MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre.
4
MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre.
5
Princess Margaret Cancer Centre.
6
Division of Cell & Molecular Biology, Toronto General Research Institute.
7
MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network.
8
The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children.
9
Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children.
10
Dept of Genetics, UT MD Anderson Cancer Center.
11
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre.
12
UHN.
13
Department of Laboratory Medicine and Pathobiology, University of Toronto.
14
Surgery, UHN.
15
National Cancer Institute.
16
MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre Gelareh.Zadeh@uhn.ca.

Abstract

PURPOSE:

HK2 is elevated in GBM and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient derived glioma stem cells, and mouse models of GBM.

EXPERIMENTAL DESIGN:

We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2 associated gene signature. We next determined the EC50 of the compounds by treating glioma cell lines and glioma stem cells. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on tumor cell metabolic activity was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, Ketoconazole and Posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo Treatment of mice bearing GBM with Ketoconazole and Posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. Additionally, treatment with azoles resulted in increased proportion of apoptotic cells.

CONCLUSIONS:

Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM., Combined with existing literature and pre-clinical results these data support the value of repurposing azoles in GBM clinical trials.

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