DNA demethylating agents synergize with oncolytic HSV1 against malignant gliomas.
OBJECTIVE
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.


METHODS
We used 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.


CONCLUSIONS
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.
Authors' Affiliations: Dardinger Center for Neuro-oncology and Neurosciences, Department of Neurological Surgery, James Cancer Hospital/Solove Research Institute/Comprehensive Cancer Center and Wexner Medical Center; Center for Biostatistics, The Ohio State University, Columbus, Ohio; and Department of Neurosurgery Institute for the Neurosciences at the Brigham, Brigham and Women's/Faulkner Hospital and Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Kazuo
K
Okemoto
Kazue
K
Kasai
Benjamin
B
Wagner
Amy
A
Haseley
Hans
H
Meisen
Chelsea
C
Bolyard
Xiaokui
X
Mo
Allison
A
Wehr
Amy
A
Lehman
Soledad
S
Fernandez
Balveen
B
Kaur
E Antonio
EA
Chiocca
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D064231:Nestin / Q000235:genetics; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D064231:Nestin; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D001374:Azacitidine