Glioblastoma-Derived Cancer Stem Cells: Treatment with Oncolytic Viruses

Abstract

Accumulating evidence suggests that many cancers are organized as a cellular hierarchy that originates from stem-like neoplastic cells capable of initiating and sustaining tumor growth. Studies have shown the presence of cancer stem cells, or cancer-initiating cells, in glioblastoma (GBM), the most malignant primary brain tumor in adults. Glioblastoma stem cells (GSCs) are characterized by abilities to efficiently generate xenografts in immunodeficient mice as well as to self-renew and commit cellular differentiation. GSCs have been shown to be resistant to conventional therapies such as radiotherapy and chemotherapy, suggesting GSCs’ contribution to tumor recurrence after current multimodal therapy. Therefore, development of therapies that target GSCs may be critical to improve outcome of GBM patients. Oncolytic viruses selectively replicate within and kill neoplastic cells while sparing normal tissues. Preclinical investigations of oncolytic viruses derived from different virus types have shown their potent anti-GBM efficacy in vitro and in rodent models of glioma. Early clinical trials have assured safety of using some of these viruses in the human brain, yet so far provided evidence for only modest efficacy, raising a question whether oncolytic viruses can target and eliminate GSCs. Our laboratory has isolated highly tumorigenic GSCs by establishing “neurosphere” cultures from human GBM specimens. Testing multiple oncolytic herpes simplex viruses (HSVs) with different genetic mutations revealed that oncolytic HSVs FΔ6 (ICP6-) and G47Δ (ICP6-, g34.5-, a47-) replicate in GSCs leading to their efficient destruction, whereas G207 (ICP6-, g34.5-) exhibits an attenuated property, demonstrating a significant impact that deletions of specific viral genes cause on oHSV efficacy against GSCs. G47Δ also suppressed clonogenic potential of GSCs that survived infection, implicating that oncolytic HSV can affect stem-like characteristics of GSCs. Moreover, using mouse models of GSC-derived GBM that include highly invasive phenotype, we showed that a single intratumoral injection of G47Δ mediates widespread infection of tumor, resulting in significant extension of survival of treated mice. These findings suggest that oncolytic HSV can be a powerful therapeutic modality toward eliminating GSCs and warrant further clinical investigation. This article reviews recent advances in oncolytic virus research specifically targeting GSCs, and discusses future directions to improve anti-GSC activities of oncolytic virus therapies.