Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus

摘要: Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance chemo-radiotherapy, effective treatment not available recurrent disease. In study we identified TMZ resistant patient-derived primary previously treated stem cells (GSC), investigated therapeutic activity a pro-apoptotic variant oHSV (oHSV-TRAIL) vitro vivo. We show that oHSV-TRAIL modulates cell survival MAP Kinase proliferation signaling pathways as well DNA damage response both TMZ-resistant GSC. Utilizing real time vivo imaging correlative immunohistochemistry, potently inhibits tumor growth extends mice bearing TMZ-insensitive intracerebral GSC tumors via robust selective induction apoptosis-mediated death cells, resulting cures 40% mice. comparison, anti-tumor effects chemoresistant model exhibiting highly invasive phenotype were significant but less prominent. This work thus demonstrates ability overcome recurrence GBM, provides basis its testing clinical trial.