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

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.

Genetically distinct glioma stem-like cell xenografts established from paired glioblastoma samples harvested before and after molecularly targeted therapy

“…Alternatively, EMT could contribute to the acquired resistance to EGFR inhibitors as implicated in lung cancer 18 . Indeed, we did observe increased expression of representative mesenchymal markers in the post-dacomitinib tumours, both in the patient and in the xenografts, as seen with other recurrent GSC xenografts 39 . Further study is necessary to determine whether an EMT-like phenomenon observed in relapsed glioblastoma is associated with resistance to targeted therapy.…”

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

“…However, we all have recognized that OHSV expression of IL-12 and its application as a monotherapy does not provide a desired therapeutic outcome, as demonstrated in several preclinical cancer models [30,84,86,148,149]. It requires synergistic or additive combination approach with other anti-cancer therapies for an improved therapeutic outcome [19,25,76,148,150,151]. Similar to OHSV-IL12, a combination immunotherapeutic approach is also required to enhance anti-tumor efficacy of other OVs encoding IL-12 [49,134,136,138,139].…”

Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma

“…To passage cells, neurospheres were dissociated with the NeuroCult Chemical Dissociation Kit (StemCell Technologies). These GSCs (not all for each feature) have been characterized by us and other investigators for sphere-forming ability and tumorigenicity 10,13,14,21,61 , epigenetic and genetic alterations 10,14,21,61,62 , gene expression and subtype classification 14,61,62 , and in vitro self-renewal 13,14,61,63 and differentiation 13,14,62 . ScGCs from the same tumor specimens as GSCs were isolated as described 13 , and grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum (FCS).…”