Highly efficacious strategy for killing glioblastoma stem cells: oncolytic virus combined with chemotherapy
Researchers at Massachusetts General Hospital and Harvard Medical School evaluated the effects of a combinatorial strategy involving the oncolytic herpes simplex virus (oHSV) G47Δ and the alkylating agent temozolomide (TMZ) on glioblastoma stem cells (GSCs). They found that combination of these agents synergistically killed GSCs in vitro and in vivo in mouse models of GSC-derived glioblastoma.
The median survival of glioblastoma multiforme (GBM), the most common primary brain tumor, is 12 to 15 months and has not improved for approximately 20 years despite optimization of multimodal therapy. Therefore, more effective drugs or treatment strategies are still needed. The data shown in this paper indicate that the combination of oHSV-G47Δ with TMZ, which is attractive for translation to clinical trials, may be a useful new approach to extend the survival of patients with GBM.
In this study, the authors reported that combination of an oncolytic virus and chemotherapeutic agent could trigger specific DNA damage response pathways to kill cancer cells, including cancer stem cells. Synergy between TMZ and oHSV-G47Δ was achieved primarily through oHSV-mediated manipulation of DNA damage responses.
The results showed that the combination of TMZ with G47Δ significantly decreased cell viability in vitro compared with TMZ or G47Δ alone in two MGMT-negative GSC lines (with high sensitivity to TMZ). Importantly, combination therapy synergistically killed both TMZ-sensitive and TMZ-resistant GSCs in the absence of MGMT-mediated DNA damage repair and, in some instances, when MSH6 was knocked down, which is a common change in recurrent GBM. Compared with TMZ or G47Δ alone, the combination strategy also prolonged the survival of mice bearing GSC-derived intracranial tumors. Notably, long-term remission was achieved in four of eight mice.
The authors suggest that their findings should be validated in other GSC lines because the five examined differed in their sensitivity to TMZ. Moreover, they report that further studies are warranted to ensure that the efficacy of treatment in immunocompetent models and patients is the same as that in athymic immunosuppressed mice. Nevertheless, this preliminary evidence suggests that combination strategies involving oHSV-G47Δ may hold significant promise as effective treatment for GBM that will prolong patient survival.
Original featured article:
Kanai R, Rabkin SD, Yip S, et al. Oncolytic virus-mediated manipulation of DNA damage responsed: synergy with chemotherapy in killing glioblastoma stem cells. J Natl Cancer Inst, 2012,104:42–55.