Treatment Of Glioblastoma Multiforme Patients Research Articles

Immunotherapeutic Approaches for the Treatment of Glioblastoma Multiforme: Mechanism and Clinical Applications

Glioma is one of the most aggressive types of primary brain tumor with a high-grade glioma known as glioblastoma multiforme (GBM). Patients diagnosed with GBM usually have an overall survival rate of less than 18 months after conventional therapy. This bleak prognosis underlines the need to consider new therapeutic interventions for GBM treatment to overcome current treatment limitations. By highlighting different immunotherapeutic approaches currently in preclinical and clinical trials, including immune checkpoint inhibitors, chimeric antigen receptors T cells, natural killer cells, vaccines, and combination therapy, this review aims to discuss the mechanisms, benefits, and limitations of immunotherapy in treating GBM patients.

Integrating ayurveda rasayana therapy with standard of care therapies in patients with glioblastoma multiforme improves caregivers' quality of life: A prospective study.

e24001 Background: Caregivers of cancer patients frequently suffer from poor quality of life (QoL) due to stress related to caregiving. This stress is more severe in patients with very aggressive cancer which has the potential to negatively affect patients' functional independence. Glioblastoma multiforme (GBM) is an incurable disease with a poor prognosis. For caregivers of patients with glioblastoma, the burden of care can be high. Integration of conventional therapy with unconventional complimentary therapies which improves Patient reported outcome measures (PROM) can significantly improve caregivers' quality of life. Hence there is a great scope of integrative therapies while treating GBM patients. The present study was conducted with an aim of evaluating the impact of an Integrative cancer care program consisting of Ayurveda and Conventional standard of care in caregivers of patients with GBM. Methods: Caregivers of patients with high-grade GBM who opted for Ayurveda Rasayana therapy after a minimum of three months of starting conventional care for GBM were included in the study. Caregiver's Quality of life was evaluated using Caregiver’s QoL score (CarGOQoL) questionnaire at baseline and after 30, 60 and 90 days of initiating the Rasayana therapy. Results: The study included 21 male and 23 female caregivers with mean age 50.8 (±2.73) years. A total of 44 patients were included at baseline whereas at the sample size at day 30,60 and 90 were 40, 37, and 33 respectively. The CarGOQoL scores showed statistically significant improvement on day 30 ( P < 0.05) which further improved on day 60 ( P< 0.01) and then remained stable (Day 60 compared with day 90 P > 0.05) on day 90. Conclusions: Caregivers of GBM showed improved QoL after integrating Ayurveda Rasayana therapy with conventional Standard of care therapies. Complimentary therapies that are known to improve PROMs in cancer patients can directly impact caregivers' QoL. Hence the possibility of an integrative approach should always be explored while treating GBM patients.

Study on the activation of cell death mechanisms: in search of new therapeutic targets in glioblastoma multiforme

Malignant primary brain tumors remain among the most difficult cancers to treat, in particular, Glioblastoma Multiforme (GBM) is the deadliest brain tumor. The standard therapies currently used are not efficient enough in improving patients’ survival and quality of life. Cisplatin (CDDP), a platinum-based drug, has shown efficacy against different solid neoplasms, but it is also associated to different forms of off-target toxicity. To overcome the limitation in the use of CDDP in the treatment of GBM patients, fourth generation platinum compounds are been synthesized, one of them is the Pt(IV)Ac-POA, a prodrug with a medium-chain fatty acid as axial ligand, which acts as a histone 3 deacetylase inhibitor. Moreover, recently, the antioxidant effects of medicinal mushrooms have been shown to induce a lowering of the toxicity of chemotherapy drugs, inducing greater therapeutic efficiency, thus the combined therapy of chemotherapy and micotherapy could be helpful in the treatment of GBM reducing the adverse effects of the former thanks to phytotherapy’s antioxidant, anti-inflammatory, immunomodulatory and antitumoral activities. Here, through immunoblotting, ultrastructural and immunofluorescence analysis, we evaluated the contribution in the activation of different cell death pathway of Micotherapy U-Care, a medicinal blend supplement, used together with platinum-based compounds on human glioblastoma U251 cells.

Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts.

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.

A Case Report on the Therapeutic Effect of Integrated Cancer Therapy for Glioblastoma Multiforme

Objective: The purpose of this report is to present the effects of integrative cancer treatment (ICT) on a patient diagnosed with glioblastoma multiforme (GBM).Methods: A 71-year-old male GBM patient received ICT from May 14 to October 12, 2021 and concurrently received temozolomide and radiotherapy. The effect on symptoms was evaluated using a visual analog scale (VAS), and changes in tumor size were assessed using magnetic resonance imaging.Results: After treatment, the VAS score for nausea decreased from 5 to 1, and the tumor size also reduced.Conclusion: ICT could be effective in treating GBM patients by reducing the size of the tumor as well as alleviating the side effects.

An oncogenic splice variant of PDGFR\u03b1 in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors

Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3’-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

Temozolomide Induces Endocytosis of EGFRvIII via p38-Mediated Non-canonical Phosphorylation in Glioblastoma Cells.

The ligand-induced internalization of epidermal growth factor receptor (EGFR) is generally considered to attenuate downstream signaling via its endosomal degradation. However, the endocytosis of an oncogenic EGFR variant III (EGFRvIII) is impaired, which leads to persistent signaling from the cell surface, thereby promoting the proliferation and survival of glioblastoma multiforme (GBM) cells. Cellular stress triggers the non-canonical endocytosis-recycling of EGFR by p38-mediated phosphorylation. In the present study, we used temozolomide (TMZ), the standard chemotherapeutic agent for the treatment of GBM patients, to examine whether EGFRvIII is controlled by a non-canonical mechanism. TMZ triggered the endocytic trafficking of serine phosphorylated EGFRvIII. Moreover, phosphorylation and endocytosis were abrogated by the selective p38 inhibitor SB203580, but not gefitinib, indicating that EGFRvIII is recruited to p38-mediated non-canonical endocytosis. The combination of TMZ and SB203580 also showed potential inhibitory effects on the proliferation and motility of glioblastoma cells.

Development of a 3 RNA Binding Protein Signature for Predicting Prognosis and Treatment Response for Glioblastoma Multiforme.

Purpose: Glioblastoma multiforme (GBM) is the most widely occurring brain malignancy. It is modulated by a variety of genes, and patients with GBM have a low survival ratio and an unsatisfactory treatment effect. The irregular regulation of RNA binding proteins (RBPs) is implicated in several malignant neoplasms and reported to exhibit an association with the occurrence and development of carcinoma. Thus, it is necessary to build a stable, multi-RBPs signature-originated model for GBM prognosis and treatment response prediction. Methods: Differentially expressed RBPs (DERBPs) were screened out based on the RBPs data of GBM and normal brain tissues from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Program (GTEx) datasets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses on DERBPs were performed, followed by an analysis of the Protein-Protein Interaction network. Survival analysis of the DERBPs was conducted by univariate and multivariate Cox regression. Then, a risk score model was created on the basis of the gene signatures in various survival-associated RBPs, and its prognostic and predictive values were evaluated through Kaplan-Meier analysis and log-rank test. A nomogram on the basis of the hub RBPs signature was applied to estimate GBM patients’ survival rates. Moreover, western blot was for the detection of the proteins. Results: BICC1, GNL3L, and KHDRBS2 were considered as prognosis-associated hub RBPs and then were applied in the construction of a prognostic model. Poor survival results appeared in GBM patients with a high-risk score. The area under the time-dependent ROC curve of the prognostic model was 0.723 in TCGA and 0.707 in Chinese Glioma Genome Atlas (CGGA) cohorts, indicating a good prognostic model. What was more, the survival duration of the high-risk group receiving radiotherapy or temozolomide chemotherapy was shorter than that of the low-risk group. The nomogram showed a great discriminating capacity for GBM, and western blot experiments demonstrated that the proteins of these 3 RBPs had different expressions in GBM cells. Conclusion: The identified 3 hub RBPs-derived risk score is effective in the prediction of GBM prognosis and treatment response, and benefits to the treatment of GBM patients.

V-ATPase as a mediator of treatment resistance in Glioblastoma Multiforme: an <em>in vitro</em> study to investigate new therapeutic strategies

Recent evidences suggest the involvement of the Vacuolar H+ ATPase (V-ATPase) in the development and/or progression of Glioblastoma Multiforme (GBM). This proton pump could be a valid therapeutic target but more in-depth studies are necessary. The aim of this study is to better define the in vitro effects on Glioma Stem Cell (GSC) primary cultures viability of single and combined treatment with Bafilomycin-A1 (Baf-A1), a V-ATPase inhibitor, and Temozolomide (TMZ), the chemotherapeutic agent currently used to treat GBM patients. We found out that GSC were resistant to TMZ and more sensitive to treatments with Baf-A1 and that the two drugs exerted a synergistic effect when administered together.

17β-estradiol induces temozolomide resistance through NRF2-mediated redox homeostasis in glioblastoma

Glioblastoma multiforme (GBM) is the most fatal cancer among brain tumors, and the standard treatment of GBM patients is surgical tumor resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. However, tumors always recur due to the developing drug resistance. It has been shown that neurosteroids, including dehydroepiandrosterone and 17β-estradiol, are synthesized in TMZ-resistant GBM tumors. Therefore, we sought to explore the possible role of 17β-estradiol in the development of drug resistance in GBM. Bioinformatics analysis revealed that aromatase/cytochrome P450 19A1 expression was gradually increased in the development from normal, astrocytoma to GBM. The level of 17β-estradiol was significantly increased in TMZ-resistant cells characterized by ultra performance liquid chromatography-tandem mass spectrometry. Furthermore, 17β-estradiol attenuated TMZ-induced cell death and reduced reactive oxygen species production by mitochondria. In addition, 17β-estradiol attenuated oxidative stress by increasing the expression of superoxide dismutase 1/2, catalase, and nuclear factor erythroid 2-related factor (NRF) 2. We found that NRF2 expression was essential for the induction of drug resistance by 17β-estradiol through the reduction of oxidative stress in GBM.

Brahma-Related Gene-1 (BRG1) promotes the malignant phenotype of glioblastoma cells.

Glioblastoma multiforme (GBM) is an aggressive malignant brain tumour that is resistant to existing therapeutics. Identifying signalling pathways deregulated in GBM that can be targeted therapeutically is critical to improve the present dismal prognosis for GBM patients. In this report, we have identified that the BRG1 (Brahma‐Related Gene‐1) catalytic subunit of the SWI/SNF chromatin remodelling complex promotes the malignant phenotype of GBM cells. We found that BRG1 is ubiquitously expressed in tumour tissue from GBM patients, and high BRG1 expression levels are localized to specific brain tumour regions. Knockout (KO) of BRG1 by CRISPR‐Cas9 gene editing had minimal effects on GBM cell proliferation, but significantly inhibited GBM cell migration and invasion. BRG1‐KO also sensitized GBM cells to the anti‐proliferative effects of the anti‐cancer agent temozolomide (TMZ), which is used to treat GBM patients in the clinic, and selectively altered STAT3 tyrosine phosphorylation and gene expression. These results demonstrate that BRG‐1 promotes invasion and migration, and decreases chemotherapy sensitivity, indicating that it functions in an oncogenic manner in GBM cells. Taken together, our findings suggest that targeting BRG1 in GBM may have therapeutic benefit in the treatment of this deadly form of brain cancer.

Different T-cell subsets in glioblastoma multiforme and targeted immunotherapy.

Glioblastoma multiforme (GBM) is a brain tumor with a high mortality rate. Surgical resection combined with radiotherapy and chemotherapy is the standard treatment for GBM patients, but the 5-year survival rate of patients despite this treatment is low. Immunotherapy has attracted increasing attention in recent years. As the pioneer and the main effector cells of immunotherapy, T cells play a key role in tumor immunotherapy. However, the T cells in GBM microenvironment are inhibited by the highly immunosuppressive environment of GBM, posing huge challenges to T cell-based GBM immunotherapy. This review summarizes the effects of the GBM microenvironment on the infiltration and function of different T-cell subsets and the possible strategies to overcome immunosuppression, and thus enhance the effectiveness of GBM immunotherapy.

Abstract 5498: The influence of computational model inaccuracies on calculated electric field distributions when simulating TTFields therapy

Abstract Introduction: TTFields are an anti-mitotic therapy designed to target solid tumors. TTFields are FDA approved for the treatment of glioblastoma multiforme (GBM) and multi-pleural mesothelioma (MPM). Delivery of TTFields in GBM patients is done by placing two pairs of transducer array on the patient's scalp. Previous studies has shown that the location of the arrays may have significant influence on the field distribution within the patient's head and tumor. Planning the placement of the arrays can hence provide better prognosis for patients. As of today, treatment of GBM patients is performed using the NovoTAL system. A new generation of patient specific planning software is currently under development. In order to plan the treatment, a computerized model is created from the patient's T1 MRI, and various options for arrays layout are simulated. The system can then asses which layout would provide the higher TTFields dose. The accuracy of these simulations may, however, depend on the accuracy of the model. Therefore there is a need to quantify how errors affect TTFields intensity distribution within the model. Methods: To test the effect of model accuracy on TTFields distribution we used a patient specific model (prepared in house) which consisted of the following tissues: scalp, skull, cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM). These tissues were automatically segmented using an in-house algorithm utilizing the MARS and SPM Matlab packages. In addition, the tumor, necrotic core and scar tissue were manually segmented into the model. To test the effect of segmentation errors on the field distribution in the tumor, we purposely inserted large defects into the model in the form of conductive (2 S/m) spheres placed at various locations within the model (i.e. WM, GM and CSF). Simulations were performed using Sim4Life v4.4 (ZMT Zurich), and the effect of the defects on the field distribution within the brain and tumor was assessed. Results: Comparison of field distributions in models into which a defect had been introduced with field distributions in the model without the defects revealed that the defects into the model perturbed the field in close vicinity to the defect s with little to no effect on the field distribution in regions that were ata distant from the defect. Typically, introducing a metallic sphere with a diameter of 2cm into altered field intensities up to a distance of abut 4cm from the center of the sphere, with little to no effect on field distributions beyond this distance. Discussion: The introduction of a metallic ball into the model represents the introduction of a very large inaccuracy in segmentation. Nonetheless, the perturbations caused by such inaccuracies seems to influence field distribution only in the immediate vicinity of the defect (up to 2cm away from it's edge). This suggests that when creating patient-specific models for planning TTFields therapy utilizing simulations, it is important to accurately segment the tissue in the vicinity of the tumor, whereas inaccuracies in regions distant from the tumor are unlikely to affect the field distribution in and around the tumor, and hence unlikely to affect the results of a planning process aimed at maximizing the field intensity within that target region. Citation Format: Ze'ev Bomzon, Ariel Naveh, Oshrit Ze'evi, Hadas S. Hershkovich. The influence of computational model inaccuracies on calculated electric field distributions when simulating TTFields therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5498.

Integrated Analysis to Evaluate the Prognostic Value of Signature mRNAs in Glioblastoma Multiforme.

BackgroundGliomas are the most common intracranial tumors and are classified as I–IV. Among them, glioblastoma multiforme (GBM) is the most common invasive glioma with a poor prognosis. New molecular biomarkers that can predict clinical outcomes in GBM patients must be identified, which will help comprehend their pathogenesis and supply personalized treatment. Our research revealed four powerful survival indicators in GBM by reanalyzing microarray data and genetic sequencing data in public databases. Moreover, it unraveled new potential therapeutic targets which could help improve the survival time and quality of life of GBM patients.Materials and Methods:To identify prognostic signatures in GBMs, we analyzed the gene profiling data of GBM and standard brain samples from the Gene Expression Omnibus, including four datasets and RNA sequencing data from The Cancer Genome Atlas (TCGA) containing 152 glioblastoma tissues. We performed the differential analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, weighted gene co-expression network analysis (WGCNA) and Cox regression analysis.ResultsAfter differential analysis in GSE12657, GSE15824, GSE42656 and GSE50161, overlapping differentially expressed genes were identified. We identified 110 up-regulated DEGs and 75 down-regulated DEGs in the GBM samples. Significantly enriched subclasses of the GO classification of these genes included mitotic sister chromatid separation, mitotic nuclear division and so on. In KEGG pathway analysis, the most abundant terms were ECM-receptor interaction and protein digestion and absorption. WGCNA analysis was performed on these 185 DEGs in 152 glioblastoma samples obtained from TCGA, and gene co-expression networks were constructed. We then performed a multivariate Cox analysis and established a Cox proportional hazards regression model using the top 20 genes significantly correlated with survival time. We identified a four-protein prognostic signature that could divide patients into high-risk and low-risk groups. Increased expression of SLC12A5, CCL2, IGFBP2, and PDPN was associated with increased risk scores. Finally, the K-M curves confirmed that these genes could be used as independent predictors of survival in patients with glioblastoma.ConclusionOur analytical study identified a set of potential biomarkers that could predict survival and may contribute to successful treatment of GBM patients.

The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism.

Glioblastoma multiforme (GBM) is the most common form of brain tumor and is very aggressive. Rapid migration and invasion of glioblastoma cells are two typical features driving malignance of GBM. Bradykinin functionally prompts calcium influx via activation of bradykinin receptor B1/B2 (BDKRB1/2). In this study, we evaluated the roles of bradykinin in migration and invasion of glioblastoma cells and the possible mechanisms. Expressions of aquaporin 4 (AQP4) mRNA and protein were upregulated in human glioblastomas. Furthermore, exposure of human U87 MG glioblastoma cells to bradykinin specifically increased levels of BDKRB1. Successively, bradykinin stimulated influx of calcium, phosphorylation of MEK1 and extracellular signal-regulated kinase (ERK)1/2, translocation and transactivation of nuclear factor-kappaB (NF-κB), and expressions of AQP4 mRNA and protein. Concomitantly, migration and invasion of human glioblastoma cells were elevated by bradykinin. Knocking-down BDKRB1 concurrently decreased AQP4 mRNA expression and cell migration and invasion. The bradykinin-induced effects were further confirmed in murine GL261 glioblastoma cells. Therefore, bradykinin can induce AQP4 expression and subsequent migration and invasion through BDKRB1-mediated calcium influx and subsequent activation of a MEK1-ERK1/2-NF-κB pathway. The bradykinin-BDKRB1 axis and AQP4 could be precise targets for treating GBM patients.

Radiothermotherapy for glioblastoma multiforme: A preliminary study

Introduction: Glioblastoma multiforme (GBM) is a highly radioresistant cancer with low survival rate. Current therapy approaches have failed to treat GBM. The aim of this study was to assess how GBM tumors respond to combination of hyperthermia and radiotherapy. Materials and Methods: In this study, 38 GBM patients were included. 19 patients were treated with 60 Gy radiations in 30 fractions and 19 patients received 60 Gy radiation and 10-12 hyperthermia seasons. Hyperthermia was done using 13.56 MHz radiofrequency radiation, with capacity electrodes. All hyperthermia regimens were delivered one hour before radiotherapy. For all patients, Karnofsky Performance Status (KPS) and tumor volumes were assessed before and 3 months after treatment. Results: Our results showed that KPS was improved in hyperthermia group rather than radiotherapy group. In regard to tumor volume changes, 2 and 3 patients had more than 50% and 20-50% decrease in tumor volume post radiotherapy respectively and 7 patients had no change. Also, 2 and 5 radiotherapy patients had more than 50% and 20-50% increase in tumor volume respectively. In hyperthermia groups 8 and 4 patients had more than 50% and 20-50% decrease in tumor volume respectively and 5 patients had no changes. In addition, 2 patients had 20-50% increase in tumor volume. Conclusion: Our results identified that combination of hyperthermia and radiation is a feasible approach to treat GBM patients and patients quality of life.

Inhibition of Radiation and Temozolomide-Induced Invadopodia Activity in Glioma Cells Using FDA-Approved Drugs

The most common primary central nervous system tumor in adults is the glioblastoma multiforme (GBM). The highly invasive nature of GBM cells is a significant factor resulting in the inevitable tumor recurrence and poor patient prognosis. Tumor cells utilize structures known as invadopodia to faciliate their invasive phenotype. In this study, utilizing an array of techniques, including gelatin matrix degradation assays, we show that GBM cell lines can form functional gelatin matrix degrading invadopodia and secrete matrix metalloproteinase 2 (MMP-2), a known invadopodia-associated matrix-degrading enzyme. Furthermore, these cellular activities were augmented in cells that survived radiotherapy and temozolomide treatment, indicating that surviving cells may possess a more invasive phenotype posttherapy. We performed a screen of FDA-approved agents not previously used for treating GBM patients with the aim of investigating their “anti-invadopodia” and cytotoxic effects in GBM cell lines and identified a number that reduced cell viability, as well as agents which also reduced invadopodia activity. Importantly, two of these, pacilitaxel and vinorelbine tartrate, reduced radiation/temozolomide-induced invadopodia activity. Our data demonstrate the value of testing previously approved drugs (repurposing) as potential adjuvant agents for the treatment of GBM patients to reduce invadopodia activity, inhibit GBM cell invasion, and potentially improve patient outcome.

Role of Intensity Modulated Radiotherapy with Concurrent and Adjuvant Chemotherapy With Temozolamide in Glioblastoma Multiforme

Background: Glioblastoma multiforme (GBM) is one of the most aggressive and common primary malignant brain tumors, comprising 16% of all primary brain and central nervous system neoplasms, with a grim prognosis despite maximal treatment. Median age of presentation is 65 years. Patients often present with symptoms of increased intracranial pressure, including headache and focal or progressive neurologic deficits. The recurrence of GBM is inevitable, its management often unclear and case dependent. The purpose of our study was to analyse the role of Intensity Modulated Radiotherapy (IMRF) with concurrent and adjuvant chemotherapy in Glioblastoma. Methods: In our study we retrospectively analysed the treatment outcome of 84 patients of Glioblastoma, treated in our institute Gandhi Medical College, Hamidia Hospital and Jawaharlal Nehru Cancer Hospital, Bhopal between July 2010-December 2014. Patients were divided into 2 groups and proper consents were taken to participate in clinical trial. A group of 42 patients were treated by traditional method of surgery and WB (Whole-brain) RT alone and other group patients were treated with maximal safe surgical resection, followed by concurrent intensity modulated radiotherapy, IMRF (started after 1 month) in 1.8–2 Gy fractions administered 5 days per week with temozolomide (TMZ) at a dose of 75 mg/m2 daily for 6 weeks and then adjuvant chemotherapy was started with TMZ 150 mg/m2 daily for 5 days for the first month. If tolerated, the dose is escalated up to 200 mg/m2 for 5 consecutive days per month for 1 year. Results: With an average follow-up of three years in 84 patients of GBM, group of patients treated with surgical resection and concurrent IMRF with TMZ, after surgery followed by adjuvant TMZ for one year demonstrated superior Progression Free Survival (PFS) of 15 months versus months with surgery and RT alone, as well as superior Overall Survival (OS) of 28 months versus 14 months with other group. The 5 year OS rate was <1% in 1st group and 5-10% in other group. Patients with WB (Whole-brain) RT developed endocrinopathy, neurocognitive toxicity and leukoencephalopathy. IFRT delivers external beam RT to the tumor with a 2–3 cm margin and hence minimises toxicity. Conclusions: This study shows the effectiveness of treating GBM patients with maximal safe surgical resection, followed by concurrent IMRF and TMZ and adjuvant chemotherapy with TMZ for long time. It not only improves PFS but also improves OS. Further understanding of underlying tumor biology is essential in developing more effective strategies. Research in gene therapy, antiangiogenic antagonists, combination chemotherapy and immunotherapies could be a ray of hope in treating GBM. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. Clinical trial identification: GMC2508IND17 Legal entity responsible for the study: Gandhi Medical College, Bhopal, India Funding: Gandhi Medical College, Bhopal, India Disclosure: All authors have declared no conflicts of interest.

Variegated Colors of Pediatric Glioblastoma Multiforme: What to Expect?

Malignant gliomas account for 35-45% of primary brain tumors; among these glioblastoma multiforme (GBM) is the most common adult brain tumor constituting approximately 85%. Its incidence is quite less in the pediatric population and treatment of these patients is particularly challenging. Exposure to ionizing radiation is the only environmental factor found to have any significant association with GBM. Several genetic alterations associated with GBM in adults have been well documented such as epidermal growth factor receptor amplification, overexpression of mouse double minute 2 homolog also known as E3 ubiquitin-protein ligase, Phosphatase and tensin homolog gene mutation, loss of heterozygosity of chromosome 10p and isocitrate dehydrogenase-1 mutation. However, data on genetic mutations in pediatric GBM is still lacking. Exophytic brain stem gliomas are rare tumors and are usually associated with a poor prognosis. The most effective treatment in achieving long-term survival in such patients, is surgical excision of the tumor and then chemoradiotherapy followed by adjuvant chemotherapy by temozolomide. This schedule is the standard treatment for GBM patients. In view of the rarity of pediatric GBM, we report here a case of pontine GBM in a 5-year-old girl.

The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma.

To date, β-catenin has been reported to be implicated in mediating the epithelial-mesenchymal transition (EMT) in a variety of human cancers, which can be triggered by EGF. However, the mechanisms underlying EGF-β-catenin pathway-induced EMT of glioblastoma multiforme (GBM) have not been reported previously. In the present study, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blot were applied to investigate the effect of EGF-β-catenin pathway on EMT of GBM. Here, we identified that β-catenin mRNA and protein levels were up-regulated in GBM tissues and four kinds of glioblastoma cell lines, including T98G, A172, U87, and U251 cells, compared with normal brain tissue and astrocytes. In U87 cell line, inhibition of β-catenin by siRNA suppressed EGF-induced proliferation, migration, invasiveness, and the expression of EMT activators (Snail and Slug). In addition, the expression of epithelial markers (E-cadherin) was up-regulated and the expression of mesenchymal markers (N-cadherin and MMP9) was down-regulated. Finally, inhibitor of PI3K/Akt signaling pathways inactivated the EGF-β-catenin-induced EMT. In conclusion, β-catenin-EMT pathway induced by EGF is important for GBM progression by the PI3K/Akt pathways. Inhibition of β-catenin leads to suppression of EGF pathway-induced EMT, which provides a new way to treat GBM patients.