Blockade of transforming growth factor-ß signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models.
Int J Cancer
; 141(11): 2348-2358, 2017 12 01.
Article
in En
| MEDLINE
| ID: mdl-28801914
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-ß) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-ß 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-ß receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-ßR 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-ßR 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-ß signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Antineoplastic Combined Chemotherapy Protocols
/
Transforming Growth Factor beta
/
Glioblastoma
/
Oncolytic Virotherapy
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Int J Cancer
Year:
2017
Document type:
Article
Affiliation country:
Morocco