Blockade of transforming growth factor‐β signaling enhances oncolytic herpes simplex virus efficacy in patient‐derived recurrent glioblastoma models. Issue 11 (26th August 2017)

• Record Type: Journal Article
• Authors: Esaki, Shinichi; Nigim, Fares; Moon, Esther; Luk, Samantha; Kiyokawa, Juri; Curry, William; Cahill, Daniel P.; Chi, Andrew S.; Iafrate, A. John; Martuza, Robert L.; Rabkin, Samuel D.; Wakimoto, Hiroaki
• Is Part Of: International journal of cancer. Volume 141:Issue 11(2017:Dec. 01)
• Page Start: 2348
• Page End: 2358
• Publication Date: 2017-08-26
• Subjects: oncolytic HSV -- recurrent glioblastoma -- TGF‐β -- JNK; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30929
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? Glioblastoma (GBM) is an aggressive disease with a high proclivity for relapse despite intensive multimodal therapy. GBM stem‐like cells (GSCs), which sustain tumor growth, are central to recurrence. This study shows that recurrent GSCs are susceptible to killing through combined treatment with oncolytic herpes simplex virus (oHSV) and a transforming growth factor beta receptor (TGF‐βR) inhibitor. In GSC‐enriched tumor spheres, GSC killing effects were found to be mediated in part through inhibitor‐induced JNK‐MAPK blockade and elevated oHSV replication. TGF‐βR inhibition further enhanced oHSV therapeutic efficacy in mice with orthotopic recurrent GBM, with long‐term tumor‐free survival in 60 percent of animals.