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Published on: September 1, 2018
The Proteasome Is Revealed as a Therapeutic Target in Recurrent Glioblastoma Xenografts
Charlotte Degorre1, Philip J Tofilon1
1Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland.
Abstract:
Radiation remains a primary treatment for glioblastoma (GBM), yet tumors frequently recur within 2 years. In this study, orthotopic xenografts initiated from glioma stem-like cells (GSC) implanted into the right striatum of nude mice were used to investigate the biology of recurrent GBM. In this model, untreated tumors showed diffuse growth pattern across the right hemisphere and olfactory bulb (OB), whereas postirradiation tumors (10 Gy) regrew predominantly within the OB, exhibiting increased cell density and a well-demarcated border indicative of an altered growth pattern. Transcriptomes of untreated and recurrent tumors were assessed using spatial profiling. Comparison of gene expression across regions of interest revealed that recurrent tumors are less heterogeneous and exhibit a distinct transcriptional profile compared with untreated tumors. A total of 463 genes were differentially expressed, and gene set enrichment analysis revealed significant enrichment of pathways related to cell-cycle regulation in the recurrent as compared with untreated tumors. Further analysis of those pathways revealed a significant upregulation of 22 proteasome-related genes in recurrent tumors. Moreover, functional assays revealed significantly higher proteasome activity in recurrent compared with untreated tumors, suggesting the proteasome as a potential therapeutic target unique to recurrent GBM. To evaluate the therapeutic relevance, mice were treated with the combination of radiation followed by the proteasome inhibitor ixazomib. Whereas ixazomib had no effect on untreated tumors, its administration after irradiation significantly prolonged survival in two GSC xenograft models. These results illustrate how defining molecular alterations that develop in recurrent GBM xenografts can lead to the identification of a novel therapeutic target.
Insights
Glioblastoma (GBM) often recurs after radiation. This study found recurrent GBM shows altered gene expression and increased proteasome activity, identifying the proteasome as a potential therapeutic target. Combining radiation with a proteasome inhibitor improved survival in models.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Genomics
Background:
- Glioblastoma (GBM) frequently recurs within two years despite radiation therapy.
- Understanding the biology of recurrent GBM is crucial for developing effective treatments.
- Glioma stem-like cells (GSCs) are implicated in GBM initiation and recurrence.
Purpose of the Study:
- To investigate the biological and transcriptional differences between untreated and recurrent GBM xenografts.
- To identify novel therapeutic targets specific to recurrent GBM.
- To evaluate the efficacy of targeting the proteasome in recurrent GBM models.
Main Methods:
- Orthotopic xenografts using GSCs in nude mice to model untreated and post-irradiation recurrent GBM.
- Spatial transcriptomic profiling to compare gene expression between untreated and recurrent tumors.
- Functional assays to measure proteasome activity.
- Therapeutic evaluation of radiation combined with the proteasome inhibitor ixazomib.
Main Results:
- Post-irradiation GBM xenografts exhibited altered growth patterns, predominantly in the olfactory bulb, with increased cell density.
- Recurrent GBM tumors were transcriptionally distinct and less heterogeneous than untreated tumors.
- Significantly upregulated proteasome-related genes and increased proteasome activity were observed in recurrent GBM.
- Combination therapy of radiation followed by ixazomib significantly prolonged survival in GSC xenograft models.
Conclusions:
- Recurrent GBM exhibits unique molecular alterations, including increased proteasome activity.
- The proteasome represents a promising therapeutic target for recurrent GBM.
- Combining radiation with proteasome inhibitors may offer a novel treatment strategy for recurrent glioblastoma.
