Identification of novel therapeutic targets in glioblastoma with functional genomic mRNA profiling.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
Cyrillo Gerardo Brahm ◽  
Anna Maria Elisabeth Walenkamp ◽  
Myra Ellen Van Linde ◽  
Henk M.W. Verheul ◽  
Rudolf Stephan Nicolaas Fehrmann
Keyword(s):  
Gene Expression ◽  
Brain Tissue ◽  
Therapeutic Targets ◽  
Current Status ◽  
Normal Brain ◽  
Functional Genomic ◽  
Normal Brain Tissue ◽  
Mrna Profiling ◽  
Class Comparison ◽  
Upregulated Genes

2018 Background: Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs and has a dismal prognosis. Therefore, there is an unmet need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets by identifying upregulated genes in GBM with known antineoplastic drug interactions. Methods: Publicly available, raw microarray expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we applied functional genomic mRNA profiling (FGmRNA-profiling), a method that is able to correct the gene expression profile of an individual tumor for physiological and experimental factors, which are considered not to be relevant for the observed tumor phenotype. Next, the FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: known interaction with antineoplastic agents and the current status of clinical evaluation in humans. Results: After FGmRNA-profiling 66 normal brain tissue samples and 1280 patient-derived GBM samples, class comparison identified 712 significantly upregulated genes. Of all significantly upregulated genes, 27 genes interacted with antineoplastic drugs. 17 out of these 27 druggable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM, and had limited efficacy. Out of the 10 remaining druggable genes, we prioritized RRM2, MAPK9 and XIAP, as these genes are associated with biologic pathways involved in the carcinogenesis of GBM and are therefore considered as novel potential therapeutic targets. Conclusions: Based on data-driven prioritization, we identified three potential therapeutic druggable targets, which have not yet been explored in the context of glioblastoma. Further preclinical and clinical research on the inhibition of these druggable genes is necessary and may lead to an improvement of treatment outcomes for patients with GBM.

scholarly journals Data-driven prioritization and preclinical evaluation of therapeutic targets in glioblastoma

2020 ◽  
Author(s):  
Cyrillo G Brahm ◽  
U Kulsoom Abdul ◽  
Megan Houweling ◽  
Myra E van Linde ◽  
Tonny Lagerweij ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Antineoplastic Agents ◽  
Unmet Need ◽  
Therapeutic Targets ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Dismal Prognosis ◽  
Upregulated Genes

Abstract Background Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM. Methods mRNA expression data of patient-derived GBM (n = 1,279) and normal brain tissue (n = 46) samples were collected from GEO and TCGA. Functional genomic mRNA (FGmRNA) profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on 1) known interactions with anti-neoplastic drugs, 2) current drug development status in humans, and 3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo. Results We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interactions with antineoplastic agents. 17 out of the 27 genes, including EGFR and VEGFA, have been clinically evaluated in GBM with limited efficacy. For the remaining ten genes, RRM2, MAPK9 (JNK2, SAPK1a), and XIAP play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth. Conclusions The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.

scholarly journals Neuroinflammatory changes of the normal brain tissue in cured mice following combined radiation and anti-PD-1 blockade therapy for glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariano Guardia Clausi ◽  
Alexander M. Stessin ◽  
Zirun Zhao ◽  
Stella E. Tsirka ◽  
Samuel Ryu
Keyword(s):  
Brain Tissue ◽  
Cranial Irradiation ◽  
Subcortical White Matter ◽  
Glioma Cell Line ◽  
Hippocampal Neurogenesis ◽  
Normal Brain ◽  
Long Term Effects ◽  
Normal Brain Tissue ◽  
Molecule Inhibitor

AbstractThe efficacy of combining radiation therapy with immune checkpoint inhibitor blockade to treat brain tumors is currently the subject of multiple investigations and holds significant therapeutic promise. However, the long-term effects of this combination therapy on the normal brain tissue are unknown. Here, we examined mice that were intracranially implanted with murine glioma cell line and became long-term survivors after treatment with a combination of 10 Gy cranial irradiation (RT) and anti-PD-1 checkpoint blockade (aPD-1). Post-mortem analysis of the cerebral hemisphere contralateral to tumor implantation showed complete abolishment of hippocampal neurogenesis, but neural stem cells were well preserved in subventricular zone. In addition, we observed a drastic reduction in the number of mature oligodendrocytes in the subcortical white matter. Importantly, this observation was evident specifically in the combined (RT + aPD-1) treatment group but not in the single treatment arm of either RT alone or aPD-1 alone. Elimination of microglia with a small molecule inhibitor of colony stimulated factor-1 receptor (PLX5622) prevented the loss of mature oligodendrocytes. These results identify for the first time a unique pattern of normal tissue changes in the brain secondary to combination treatment with radiotherapy and immunotherapy. The results also suggest a role for microglia as key mediators of the adverse treatment effect.

Quantitative Measurements of Regional Glucose Utilization and Rate of Valine Incorporation into Proteins by Double-Tracer Autoradiography in the Rat Brain Tumor Model

1989 ◽  
Vol 9 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Michihiro Kirikae ◽  
Mirko Diksic ◽  
Y. Lucas Yamamoto
Keyword(s):  
Protein Synthesis ◽  
Brain Tumor ◽  
Rat Brain ◽  
Brain Tissue ◽  
Glucose Utilization ◽  
Tumor Model ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Rat Brain Tumor ◽  
Brain Tumor Model

We examined the rate of glucose utilization and the rate of valine incorporation into proteins using 2-[18F]fluoro-2-deoxyglucose and L-[1-14C]-valine in a rat brain tumor model by quantitative double-tracer autoradiography. We found that in the implanted tumor the rate of valine incorporation into proteins was about 22 times and the rate of glucose utilization was about 1.5 times that in the contralateral cortex. (In the ipsilateral cortex, the tumor had a profound effect on glucose utilization but no effect on the rate of valine incorporation into proteins.) Our findings suggest that it is more useful to measure protein synthesis than glucose utilization to assess the effectiveness of antitumor agents and their toxicity to normal brain tissue. We compared two methods to estimate the rate of valine incorporation: “kinetic” (quantitation done using an operational equation and the average brain rate coefficients) and “washed slices” (unbound labeled valine removed by washing brain slices in 10% thrichloroacetic acid). The results were the same using either method. It would seem that the kinetic method can thus be used for quantitative measurement of protein synthesis in brain tumors and normal brain tissue using [11C]-valine with positron emission tomography.

PET Study of Methionine Accumulation in Glioma and Normal Brain Tissue

1987 ◽  
Vol 11 (2) ◽  
pp. 208-213 ◽  
Author(s):  
Mats Bergström ◽  
Kaj Ericson ◽  
Lars Hagenfeldt ◽  
Mikael Mosskin ◽  
Hans von Holst ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Normal Brain ◽  
Normal Brain Tissue

Quantitative Analysis of Mobile Proteins in Normal Brain Tissue by Amide Proton Transfer Imaging

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Kazuaki Sugawara ◽  
Tosiaki Miyati ◽  
Ryo Ueda ◽  
Daisuke Yoshimaru ◽  
Masanobu Nakamura ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Proton Transfer ◽  
Brain Tissue ◽  
Amide Proton ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Amide Proton Transfer ◽  
Amide Proton Transfer Imaging

scholarly journals Glutathione S-Transferases and Cytochrome P450 Enzyme Expression in Patients with Intracranial Tumors: Preliminary Report of 55 Patients

2018 ◽  
Vol 28 (1) ◽  
pp. 56-62
Author(s):  
Cahit Kural ◽  
Arzu Kaya Kocdogan ◽  
Gulcin Güler Şimşek ◽  
Serpil Oğuztüzün ◽  
Pınar Kaygın ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Brain Tissue ◽  
Pituitary Adenomas ◽  
Normal Brain ◽  
Cytochrome P450 Enzyme ◽  
Intracranial Tumors ◽  
Glutathione S Transferase ◽  
Normal Brain Tissue ◽  
Tissue Samples ◽  
P450 Enzyme

Objective: Intracranial tumors are one of the most frightening and difficult-to-treat tumor types. In addition to surgery, protocols such as chemotherapy and radiotherapy also take place in the treatment. Glutathione S-transferase (GST) and cytochrome P450 (CYP) enzymes are prominent drug-metabolizing enzymes in the human body. The aim of this study is to show the expression of GSTP1, GSTM1, CYP1A1, and CYP1B1 in different types of brain tumors and compare our results with those in the literature. Subjects and Methods: The expression of GSTP1, GSTM1, CYP1A1, and CYP1B1 was analyzed using immunostaining in 55 patients with intracranial tumors in 2016–2017. For GST and CYP expression in normal brain tissue, samples of a portion of surrounding normal brain tissue as well as a matched far neighbor of tumor tissue were used. The demographic features of the patients were documented and the expression results compared. Results: The mean age of the patients was 46.72 years; 29 patients were female and 26 were male. Fifty-seven specimens were obtained from 55 patients. Among them, meningioma was diagnosed in 12, metastases in 12, glioblastoma in 9, and pituitary adenoma in 5. The highest GSTP1, GSTM1, and CYP­1A1 expressions were observed in pituitary adenomas. The lowest GSTP1 expression was detected in glioblastomas and the lowest CYP1B1 expression in pituitary adenomas. Conclusion: GSTP1 and CYP expression is increased in intracranial tumors. These results should be confirmed with a larger series and different enzyme subtypes.

scholarly journals Differential expression of protein phosphatase PPM1B and multiple protein phosphatase regulatory subunits in glioblastoma.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Brain Tissue ◽  
Protein Phosphatase ◽  
Treatment Options ◽  
Normal Brain ◽  
Regulatory Subunits ◽  
Gene Expression Information ◽  
Multiple Protein ◽  
Substrate Phosphorylation ◽  
Public Dataset

Glioblastoma multiforme is an aggressive brain cancer with few treatment options and poor survival outcomes (1, 2). We used a public dataset (3) containing the gene expression information of tumors from 17 patients diagnosed with glioblastoma and compared it to the gene expression information from the non-cancerous, healthy brain tissue from 8 individuals as a reference control, to understand what is most different between the transcriptional behavior of glioblastoma tumors relative to the tissue it arises from. We found that protein phosphatase PPM1B and three protein phosphatase regulatory subunits were among the genes whose expression was most different between glioblastoma tumors and “normal” brain tissue. The fact that multiple phosphatase regulatory genes are expressed at significantly lower levels in glioblastoma tumors suggests that alteration of substrate phosphorylation might be an important event in glioblastoma formation, maintenance or progression.

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