Abstract P4-05-01: Oncolytic Herpes Simplex Virus Vector G47Δ Effectively Targets Breast Cancer Stem Cells

Abstract

Abstract Breast tumors can be classified according to their gene-expression profiles into different molecular subtypes with distinct biological and clinical features. Moreover, different subtypes show distinct responses to different therapeutic regimens, thereby resulting in markedly different outcomes. Recently, accumulating evidence has suggested that breast cancer originates from cancer stem cells (CSCs), which comprise a small percentage of the overall tumor but are highly tumorigenic and pluripotent with unlimited proliferation potential. Furthermore, cancer stem cells are highly resistant to conventional treatment, which potentially explains certain difficulties in treating cancer with current therapy options. The use of oncolytic viruses is a relatively new strategy in cancer therapy, oncolytic herpes simplex virus (oHSV) has been shown to be a safe and effective therapeutic approach for a variety of different cancers. In this study, different types of breast cancer cell lines were cultured in anchorage-independent conditions, the cells typically form mammospheres within 10 days of anchorage-independent culture, which showed properties of CSCs. The mammospheres are capable of being passaged indefinitely and single dissociated mammosphere cells were able to regenerate spheres. Moreover, compared to the parental cell lines, mammoshpere cells were enriched for CD44+CD24− cells and highly expression of the alternative breast cancer stem cell marker ALDH-1. The third generation oHSV vector G47Δ effectively killed different subtypes of breast cancer cells in vitro, with more than 98% of the tumor cells killed by day 5, even at multiplicities of infection(MOI) 0.01. Moreover, G47Δ equally targeted non-cancer stem cells (NCSCs) and CSCs which showed resistance to paclitaxel. We also demonstrated that G47Δ effectively replicated and spread among CSCs. Moreover, G47Δ impaired the self-renewal ability of CSCs, as the viable cells unable to form secondary tumor spheres. We also showed that G47Δ was able to induce the regression of tumor xenografts in BALB/c nude mice and demonstrated the ability of G47Δ to synergize with paclitaxel for killing both NCSCs and CSCs. This is the first report that oHSV effectively targets different breast cancer NCSCs and CSCs, thereby suggesting that oHSV may be an effective treatment modality for patients with breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-05-01.