Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus.

Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.

Jahan N ，Lee JM ，Shah K ，Wakimoto H ... -  《-》

Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells.

Kanai R ，Rabkin SD ，Yip S ，Sgubin D ，Zaupa CM ，Hirose Y ，Louis DN ，Wakimoto H ，Martuza RL ... -  《-》

Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors.

Tamura K ，Wakimoto H ，Agarwal AS ，Rabkin SD ，Bhere D ，Martuza RL ，Kuroda T ，Kasmieh R ，Shah K ... -  《-》

Blockade of transforming growth factor-β signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models.

Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF-β) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-β inhibitors would synergistically exert antitumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after postsurgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF-β receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-βR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF-βR inhibitor greatly enhanced the antitumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF-β signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients.

Esaki S ，Nigim F ，Moon E ，Luk S ，Kiyokawa J ，Curry W Jr ，Cahill DP ，Chi AS ，Iafrate AJ ，Martuza RL ，Rabkin SD ，Wakimoto H ... -  《-》

Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors.

Wakimoto H ，Kesari S ，Farrell CJ ，Curry WT Jr ，Zaupa C ，Aghi M ，Kuroda T ，Stemmer-Rachamimov A ，Shah K ，Liu TC ，Jeyaretna DS ，Debasitis J ，Pruszak J ，Martuza RL ，Rabkin SD ... -  《-》