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

Purpose: Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), 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 antitumor activity and limit drug toxicity. Experimental Design: In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47 Delta 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 histologic detection of apoptosis. Results: GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47 Delta was similar. Combining G47 Delta 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 G47 Delta significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors. Conclusions: The combination of low-dose etoposide with G47 Delta 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. Clin Cancer Res; 17(23); 7383-93. (C)2011 AACR.