Abstract: 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.
Keywords: Animals; Apoptosis/physiology; Brain Neoplasms/drug therapy/*therapy/virology; Cell Line, Tumor; Cohort Studies; Dacarbazine/analogs & derivatives/pharmacology; Drug Resistance, Neoplasm; Glioblastoma/drug therapy/*therapy/virology; HEK293 Cells; Humans; Mice; Neoplasm Recurrence, Local/drug therapy/therapy/virology; Neoplastic Stem Cells/drug effects/pathology/*virology; Oncolytic Virotherapy/*methods; Simplexvirus/genetics/*physiology; TNF-Related Apoptosis-Inducing Ligand/biosynthesis/genetics; TNF-related apoptosis inducing ligand (TRAIL); glioblastoma; oncolytic herpes simplex virus; recurrence; temozolomide