TY - JOUR
T1 - DNA demethylating agents synergize with oncolytic HSV1 against malignant gliomas
AU - Okemoto, Kazuo
AU - Kasai, Kazue
AU - Wagner, Benjamin
AU - Haseley, Amy
AU - Meisen, Hans
AU - Bolyard, Chelsea
AU - Mo, Xiaokui
AU - Wehr, Allison
AU - Lehman, Amy
AU - Fernandez, Soledad
AU - Kaur, Balveen
AU - Chiocca, E. Antonio
PY - 2013/11/1
Y1 - 2013/11/1
N2 - Purpose: Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. Experimental Design:Weused demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. Results: The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. Conclusion: These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma.
AB - Purpose: Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. Experimental Design:Weused demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. Results: The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. Conclusion: These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma.
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U2 - 10.1158/1078-0432.CCR-12-3588
DO - 10.1158/1078-0432.CCR-12-3588
M3 - Article
C2 - 24056786
AN - SCOPUS:84887116567
SN - 1078-0432
VL - 19
SP - 5952
EP - 5959
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -