TY  - JOUR
AU  - Jahan, N.
AU  - Lee, J.M.
AU  - Shah, K.
AU  - Wakimoto, H.
PY  - 2017//
TI  - Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus
T2  - Int J Cancer
JO  - International Journal of Cancer
SP  - 1671
EP  - 1681
VL  - 141
IS  - 8
KW  - Animals
KW  - Apoptosis/physiology
KW  - Brain Neoplasms/drug therapy/*therapy/virology
KW  - Cell Line
KW  - Tumor
KW  - Cohort Studies
KW  - Dacarbazine/analogs &amp
KW  - derivatives/pharmacology
KW  - Drug Resistance
KW  - Neoplasm
KW  - Glioblastoma/drug therapy/*therapy/virology
KW  - HEK293 Cells
KW  - Humans
KW  - Mice
KW  - Neoplasm Recurrence
KW  - Local/drug therapy/therapy/virology
KW  - Neoplastic Stem Cells/drug effects/pathology/*virology
KW  - Oncolytic Virotherapy/*methods
KW  - Simplexvirus/genetics/*physiology
KW  - TNF-Related Apoptosis-Inducing Ligand/biosynthesis/genetics
KW  - TNF-related apoptosis inducing ligand (TRAIL)
KW  - glioblastoma
KW  - oncolytic herpes simplex virus
KW  - recurrence
KW  - temozolomide
AB  - Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.
SN  - 0020-7136
UR  - http://www.ncbi.nlm.nih.gov/pubmed/28567859
UR  - PM:28567859
N1  - PMID:28567859
ID  - Jahan_etal2017
ER  -