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

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

Int J Cancer. 2017 Aug 12;:

Authors: Esaki S, Nigim F, Moon E, Luk S, Kiyokawa J, Curry W, Cahill DP, Chi AS, Iafrate AJ, Martuza RL, Rabkin SD, Wakimoto H

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 anti-tumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after post-surgical 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 anti-tumor 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. This article is protected by copyright. All rights reserved.

PMID: 28801914 [PubMed - as supplied by publisher]

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