Enhanced Antitumor Efficacy of Low-Dose Etoposide with Oncolytic Herpes Simplex Virus in Human Glioblastoma Stem Cell Xenografts

Abstract

Purpose Glioblastoma (GBM) inevitably recurs despite surgery, radiation and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSCs), has been implicated in this recurrence. The chemotherapeutic agent, etoposide is generally reserved for treating recurrent tumors, however its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low dose etoposide with an oncolytic HSV to enhance anti-tumor activity and limit drug toxicity. Experimental design In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oHSV-G47Δ alone or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events and histological detection of apoptosis. Results GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, while their sensitivity to G47Δ was similar. Combining G47Δ with low dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low dose etoposide with G47Δ significantly extended survival of mice bearing etoposide-insensitive intracranial human GSC-derived tumors. Conclusions The combination of low dose etoposide with G47Δ increases survival of mice bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.

Polo-Like Kinase 1 Inhibition Kills Glioblastoma Multiforme Brain Tumor Cells in Part Through Loss of SOX2 and Delays Tumor Progression in Mice

“…In addition, even those that were capable of primary sphere formation such as BT74, self-renewal was greatly impaired when BI2536 treatment was continued. Recently, BT74 cells have been shown to be resistant to chemotherapy and molecular-targeting agents [86,87]. Thus, our results are particularly exciting as it suggests that PLK1 inhibitor may potentially eliminate the cells that make up the bulk of the tumors as well as deplete the notoriously chemotherapy and radiation-resistant BTICs.…”

Viral therapy of glioblastoma multiforme

“…To summarize, the tumor microenvironment, particularly as it relates to the potential contribution of immune suppression, heterogeneity of cells, and, potentially, GSCs, underscores the nature of the problem. Previous studies have suggested that GSCs are susceptible to treatment with oncolytic HSV (12,13). Until this study, syngeneic models of GSCs were sparse, and none that were suitable for examination of oHSV existed.…”

Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells

“…For Chou-Talalay analysis, fixed ratios of drug and/or virus were added to cells and the relative changes in cellular metabolism were used to calculate the combination index (CI) using the CompuSyn software (Version 1; Cambridge, MA, USA). 38,39 Virus burst size HS578T cells were infected with a specific MOI of KM100. Samples were harvested and tittered as described previously.…”