Blockade of transforming growth factor-β signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models.

摘要: Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset tumor cells with stem-like properties, termed GBM (GSCs), are considered to play a role in relapse. Although oncolytic herpes simplex virus (oHSV) promising therapeutic GBM, its efficacy against incompletely characterized. Transforming growth factor beta (TGF-β) plays vital roles maintaining GSC stemness pathogenesis. We hypothesized that oHSV TGF-β inhibitors would synergistically exert antitumor effects GBM. Here we established panel patient-derived models from GBMs relapsed after postsurgical radiation chemotherapy, based on GSC-enriched sphere cultures. These GSCs resistant standard-of-care temozolomide but susceptible oHSVs G47Δ MG18L. Inhibition receptor kinase selective targeted small molecules reduced clonogenic formation all tested GSCs. The combination TGF-βR inhibitor was synergistic killing through, part, an inhibitor-induced JNK-MAPK blockade increase replication. In vivo, systemic treatment greatly enhanced single intratumoral injections, resulting cures 60% mice bearing orthotopic results reveal novel interaction signaling blockade, warrant further investigations aimed at clinical translation this strategy patients.