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Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma.

ABSTRACT: BACKGROUND:Tumor-homing tumoricidal neural stem cell (tNSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). Developing strategies for tNSC therapy to overcome intratumoral heterogeneity, variable cancer cell invasiveness, and differential drug response of GBM will be essential for efficacious treatment response in the clinical setting. The aim of this study was to create novel hybrid tumor models and investigate the impact of GBM heterogeneity on tNSC therapies. METHODS:We used organotypic brain slice explants and distinct human GBM cell types to generate heterogeneous models ex vivo and in vivo. We then tested the efficacy of mono- and combination therapy with primary NSCs and fibroblast-derived human induced neural stem cells (iNSCs) engineered with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or enzyme-prodrug therapy. RESULTS:Optical imaging, molecular assays, and immunohistochemistry revealed that the hybrid models recapitulated key aspects of patient GBM, including heterogeneity in TRAIL sensitivity, proliferation, migration patterns, hypoxia, blood vessel structure, cancer stem cell populations, and immune infiltration. To explore the impact of heterogeneity on tNSC therapy, testing in multiple in vivo models showed that tNSC-TRAIL therapy potently inhibited tumor growth and significantly increased survival across all paradigms. Patterns of tumor recurrence varied with therapeutic (tNSC-TRAIL and/or tNSC-thymidine kinase), dose, and route of administration. CONCLUSIONS:These studies report new hybrid models that accurately capture key aspects of GBM heterogeneity which markedly impact treatment response while demonstrating the ability of tNSC mono- and combination therapy to overcome certain aspects of heterogeneity for robust tumor kill.

SUBMITTER: Satterlee AB

PROVIDER: S-EPMC6917409 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma.

Satterlee Andrew B AB Dunn Denise E DE Lo Donald C DC Khagi Simon S Hingtgen Shawn S

Neuro-oncology 20191201 12

<h4>Background</h4>Tumor-homing tumoricidal neural stem cell (tNSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). Developing strategies for tNSC therapy to overcome intratumoral heterogeneity, variable cancer cell invasiveness, and differential drug response of GBM will be essential for efficacious treatment response in the clinical setting. The aim of this study was to create novel hybrid tumor models and investigate the impact of GBM he ...[more]

PMID: 31420675

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Project description:BackgroundAlthough both the alkylating agent temozolomide (TMZ) and oncolytic viruses hold promise for treating glioblastoma, which remains uniformly lethal, the effectiveness of combining the two treatments and the mechanism of their interaction on cancer stem cells are unknown.MethodsWe investigated the efficacy of combining TMZ and the oncolytic herpes simplex virus (oHSV) G47? in killing glioblastoma stem cells (GSCs), using Chou-Talalay combination index analysis, immunocytochemistry and fluorescence microscopy, and neutral comet assay. The role of treatment-induced DNA double-strand breaks, activation of DNA damage responses, and virus replication in the cytotoxic interaction between G47? and TMZ was examined with a panel of pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of DNA repair pathways. Comparisons of cell survival and virus replication were performed using a two-sided t test (unpaired). The survival of athymic mice (n = 6-8 mice per group) bearing GSC-derived glioblastoma tumors treated with the combination of G47? and TMZ was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test.ResultsThe combination of G47? and TMZ acted synergistically in killing GSCs but not neurons, with associated robust induction of DNA damage. Pharmacological and shRNA-mediated knockdown studies suggested that activated ataxia telangiectasia mutated (ATM) is a crucial mediator of synergy. Activated ATM relocalized to HSV DNA replication compartments where it likely enhanced oHSV replication and could not participate in repairing TMZ-induced DNA damage. Sensitivity to TMZ and synergy with G47? decreased with O(6)-methylguanine-DNA-methyltransferase (MGMT) expression and MSH6 knockdown. Combined G47? and TMZ treatment extended survival of mice bearing GSC-derived intracranial tumors, achieving long-term remission in four of eight mice (median survival = 228 days; G47? alone vs G47? + TMZ, hazard ratio of survival = 7.1, 95% confidence interval = 1.9 to 26.1, P = .003) at TMZ doses attainable in patients.ConclusionsThe combination of G47? and TMZ acts synergistically in killing GSCs through oHSV-mediated manipulation of DNA damage responses. This strategy is highly efficacious in representative preclinical models and warrants clinical translation.

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Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma.

Publications

Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma.

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