Efficacy Of Radiotherapy In Glioblastoma Research Articles

A Stemness-Related Gene Signature to Predict Treatment Efficacy of Radiotherapy in Glioblastoma

<h3>Purpose/Objective(s)</h3> It is known that cancer stem cells contribute to disease progression and treatment resistance. However, the clinical value of stemness in glioblastoma (GBM) has not been fully elucidated. Here, we attempted to construct a stemness-related gene signature (SRGS) based on the expression profile of genes to predict the treatment efficacy of radiotherapy in GBM. <h3>Materials/Methods</h3> Transcriptome data and corresponding clinical information of GBM patients were extracted from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) database. These stemness-related genes with both differentially expression and prognostic value were used to construct the stemness-related gene signature (SRGS). The performance of the SRGS was evaluated using Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves and correlation analysis of molecular characteristics, while the TCGA database was used for external validation. Next, we evaluated the predictive value of SRGS for treatment efficacy of radiotherapy in GBM. <h3>Results</h3> The prognostic gene signature was composed of nine genes, including ASPM, EPHA1, LIF, LOXL2, NAP1L2, OTP, PITX2, RDH10 and RUNX1. Patients were divided into high and low-risk groups according to the median risk score of SRGS. Patients in the high-risk group had significantly poor overall survival (OS) than that of patients in the low-risk group (1-year OS, 46.3% vs. 53.8%, P=0.018; 2-year OS, 17.2% vs. 34.2%, P=0.002; 3-year OS 6.7% vs. 26.2%, P<0.001). Meanwhile, the area under the ROC curves of the SRGS was 0.603, 0.724, and 0.763 for 1-, 2-, and 3-year OS in the CGGA cohort, and demonstrated stable consistency in the TCGA external validation. In the high-risk group, patients receiving radiotherapy had better OS than those without receiving radiotherapy (1-year OS, 58.0% vs. 23.8%, P=0.001; 2-year OS, 19.7% vs. 4.8%, P=0.016; 3-year OS, 9.9% vs. 0.0%, P<0.001). However, radiotherapy failed to improve OS in low-risk group, with no statistically significant differences in cohorts between radiotherapy and without radiotherapy at 1 year OS, 50.0% vs. 44.4%, P=0.396; 2-years OS, 33.0% vs. 22.4%, P=0.427; 3-years OS, 24.8% vs. 13.5%, P=0.397). Higher risk scores of SRGS were observed in patients with wild-type IDH1, unmethylated MGMT promoter and 1p/19q non-codeletion, respectively. Multivariate analysis found SRGS was an independently prognostic factor of OS for GBM. <h3>Conclusion</h3> We constructed and validated a novel stemness-related gene signature. Moreover, this gene signature could predict the treatment efficacy of radiotherapy for GBM.

DNA Tamir Mekanizması İlişkili Genlerin Biyoinformatik Yöntemlerle Glioblastomda Tanımlanması

Amaç: DNA tamir mekanizmalarında (DTM) görev alan genlerin ifade değişimleri glioblastomda (GBM) radyoterapi direnci ile ilişkilendirilmiştir. DTM’de rol oynayan genlerin biyoinformatik yöntemlerle tanımlanması GBM tedavisinde kullanılabilecek potansiyel yeni hedeflerin belirlenmesine yardımcı olabilir. Bu çalışmanın amacı, DNA tamir mekanizmalarında rol oynayan genlerin biyoinformatik yöntemler kullanılarak GBM tümörlerinde tanımlanmasıdır. Yöntem: DNA tamiri mekanizmaları ile ilişkili genler “Reactome” ve “KEGG” veri tabanları üzerinde tanımlandı. GBM tümörlerinde genlere ait mRNA ifade profilleri GEO GDS1813 ve GDS2853 veri setlerinde “Orange Canvas” yazılımı kullanılarak incelendi. Genlerdeki genetik değişimler cBioPortal veri tabanı kullanılarak GBM TCGA olgularında tanımlandı. GEPIA2, değişen gen ifadelerinin TCGA GBM hasta sağ kalım süreleri üzerindeki etkisini göstermek için kullanıldı. Bulgular: ERCC6, FAN1, MBD4, PARP1 ve UNG genlerinin mRNA ifade profillerinin GBM tümörlerinde değişime uğradığı bulundu. Tanımlanan genler için farklı tipte mutasyonlar ve kopya sayı değişimleri TCGA GBM olgularında gözlendi. Yüksek ve düşük gen ifade profillerinin GBM hastalarının genel ve hastalıksız sağ kalım süreleri üzerinde etkisi olmadığı saptandı. Sonuç: Bu çalışmada tanımlanan ERCC6, PARP1 ve UNG genleri baskılanması durumunda GBM’de radyoterapi etkinliğini arttırabilecek potansiyel birer terapötik hedef olabilir.

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors.

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.

Inhibition of Colony-Stimulating Factor-1 Receptor Enhances the Efficacy of Radiotherapy and Reduces Immune Suppression in Glioblastoma.

To use inhibition of colony-stimulating factor-1 receptor (CSF-1R) to target tumor-associated macrophages (TAMs) and improve the efficacy of radiotherapy in glioblastoma (GBM). The CSF-1R inhibitor BLZ-945 was used to examine the impact of CSF-1R inhibition on M2 polarization in vitro. Using an orthotopic, immunocompetent GBM model, mice were treated with vehicle, RT, BLZ-945, or RT plus BLZ-945. BLZ-945 reduced M2 polarization in vitro. BLZ-945 alone did not improve median overall survival (mOS=29 days) compared to control mice (mOS=27 days). RT improved survival (mOS=45 days; p=0.02), while RT plus BLZ-945 led to the longest survival (mOS=not reached; p=0.005). Resected tumors had a relatively large population of M2 TAMs in GBM at baseline, which was increased in response to RT. BLZ-945 reduced RT-induced M2 infiltration. Inhibition of CSF-1R improved response to RT in the treatment of GBM and may represent a promising strategy to improve RT-induced antitumor immune responses.

The small molecule drug CBL0137 increases the level of DNA damage and the efficacy of radiotherapy for glioblastoma.

Glioblastoma (GBM) is an incurable brain tumor with inevitable recurrence. This is in part due to a highly malignant cancer stem cell (CSC) subpopulation of tumor cells that is particularly resistant to conventional treatments, including radiotherapy. Here we show that CBL0137, a small molecule anti-cancer agent, sensitizes GBM CSCs to radiotherapy. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex to chromatin, resulting in cytotoxicity preferentially within tumor cells. We show that when combined with radiotherapy, CBL0137 inhibited GBM CSC growth and resulted in more DNA damage in the CSCs compared to irradiation or drug alone. Using an in vivo subcutaneous model, we showed that the frequency of GBM CSCs was reduced when tumors were pretreated with CBL0137 and then exposed to irradiation. Survival studies with orthotopic GBM models resulted in significantly extended survival for mice treated with combinatorial therapy. As GBM CSCs contribute to the inevitable recurrence in patients, targeting them is imperative. This work establishes a new treatment paradigm for GBM that sensitizes CSCs to irradiation and may ultimately reduce tumor recurrence.

Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma

BackgroundRadiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM.MethodsMicroarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines.ResultsRab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner.ConclusionsOur results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.

Glucocorticoids promote DNA repair to reduce efficacy of radiotherapy in Glioblastoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

ID1 affects the efficacy of radiotherapy in glioblastoma through inhibition of DNA repair pathways

Glioblastoma multiforme (GBM) is characterized by poor therapeutic response and poor overall survival. It is crucial that more effective therapies be developed for the treatment of GBM. Inhibitor of DNA binding protein-1 (ID1) has been shown to maintain the self-renewal capacity of neural stem cells and might be involved in the therapeutic resistance of GBM. In the present study, we explored survival data from the The Cancer Genome Atalas database that were based on ID1 expression for patients diagnosed with primary GBMs. Interestingly, patients with high ID1 expression had better survival than patients with low ID1 expression, and a strong correlation was found between radiotherapy efficacy, ID1 expression, and overall survival. We further investigated the relationship between ID1 expression and the radiosensitivity of glioblastoma using glioblastoma cell lines. The clonogenic formation assay showed that U87 ID1-shRNA cells were much less sensitive to radiation. Moreover, both the results of the γH2AX foci staining assay and the comet assay further revealed that ID1 negatively regulates DNA repair processes by downregulating the expression of genes such as DNA ligase IV (LIG4) and ataxia-telangiectasia-mutated. Additionally, ID1 induces G2/M arrest in U87 cells. Taken together, these results suggest that ID1 may be a new prognostic marker for GBM and have important implications for the therapeutic strategies used to treat GBM patients.