The Role of Kinase Signaling in Resistance to Bevacizumab Therapy for Glioblastoma Multiforme

Ramezani, Sara; Vousooghi, Nasim; Joghataei, Mohammad Taghi; Chabok, Shahrokh Yousefzadeh

doi:10.1089/cbr.2018.2651

Cited by 18 publications

(16 citation statements)

References 128 publications

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“…Blood vessels are considered a key therapeutic target in glioblastoma and many other cancers, based on the concept that starving a tumor of its blood supply should result in tumor shrinkage or even elimination. Indeed, the angiogenesis inhibitor bevacizumab (Avastin) has been approved by the United States Food and Drug Administration (FDA) for the treatment of glioblastoma, but clinical responses to this treatment are generally limited because of resistance mechanisms that develop within the tumor over time 68 . We propose that FAP‐targeted immunotherapy could be a more effective approach to targeting the glioblastoma vasculature by facilitating the rapid and selective physical destruction of existing tumor blood vessels, including their supporting perivascular network, rather than aiming to block a pro‐angiogenic signalling pathway that tumors can evolve to survive without.…”

Section: Discussionmentioning

confidence: 99%

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy

Ebert

Gargett

et al. 2020

Clin & Trans Imm

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Objectives. Targeted immunotherapies such as chimeric antigen receptor (CAR)-T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples. Methods. Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets. Short-term cultures of glioma neural stem (GNS) cells were compared to cultures of healthy astrocytes and neurons using flow cytometry. Glioblastoma tissues were dissociated and analysed by highparameter flow cytometry and single-cell transcriptomics (scRNAseq). Results. Compared to normal brain, FAP was overexpressed at the gene and protein level in a large percentage of glioblastoma tissues, with highest levels of expression associated with poorer prognosis. FAP was also overexpressed in several paediatric brain cancers. FAP was commonly expressed by cultured GNS cells but absent from normal neurons and astrocytes. Within glioblastoma tissues, the strongest expression of FAP was around blood vessels. In fact, almost every tumor vessel was highlighted by FAP expression, whereas normal tissue vessels and cultured endothelial cells (ECs) lacked expression. Single-cell

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Section: Discussionmentioning

confidence: 99%

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy

Ebert

Gargett

et al. 2020

Clin & Trans Imm

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“…Therapy using bevacizumab is an option for preventing metastasis ( Huang et al, 2017 ). However, the development of resistance by glioblastoma cells causes a decrease in the effectiveness of bevacizumab and increases mortality in glioblastoma patients ( Ramezani et al, 2019 ). Therefore, researchers continue to try to find adjuvant for glioblastoma therapy.…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of potential targets of the curcumin analog pentagamavunon-1 (PGV-1) in overcoming resistance of glioblastoma cells to bevacizumab

Hermawan

Putri

2021

Saudi Pharmaceutical Journal

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Background Glioblastoma is one of the most aggressive and deadliest malignant tumors. Acquired resistance decreases the effectiveness of bevacizumab in glioblastoma treatment and thus increases the mortality rate in patients with glioblastoma. In this study, the potential targets of pentagamavunone-1 (PGV-1), a curcumin analog, were explored as a complementary treatment to bevacizumab in glioblastoma therapy. Methods Target prediction, data collection, and analysis were conducted using the similarity ensemble approach (SEA), SwissTargetPrediction, STRING DB, and Gene Expression Omnibus (GEO) datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using Webgestalt and DAVID, respectively. Hub genes were selected based on the highest degree scores using the CytoHubba. Analysis of genetic alterations and gene expression as well as Kaplan–Meier survival analysis of selected genes were conducted with cBioportal and GEPIA. Immune infiltration correlations between selected genes and immune cells were analyzed with database TIMER 2.0. Results We found 374 targets of PGV-1, 1139 differentially expressed genes (DEGs) from bevacizumab-resistant-glioblastoma cells. A Venn diagram analysis using these two sets of data resulted in 21 genes that were identified as potential targets of PGV-1 against bevacizumab resistance (PBR). PBR regulated the metabolism of xenobiotics by cytochrome P450. Seven potential therapeutic PBR, namely GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110 were found to have genetic alterations in 1.2%–30% of patients with glioblastoma. Analysis using the GEPIA database showed that the mRNA expression of ADAM10 , AKR1B1 , and HSD17B10 was significantly upregulated in glioblastoma patients. Kaplan–Meier survival analysis showed that only patients with low mRNA expression of AKR1B1 had significantly better overall survival than the patients in the high mRNA group. We also found a correlation between PBR and immune cells and thus revealed the potential of PGV-1 as an immunotherapeutic agent via targeting of PBR. Conclusion This study highlighted seven PBR, namely, GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110. This study also emphasized the potential of PBR as a target for immunotherapy with PGV-1. Further validation of the results of this study is required for the development of PGV-1 as an adjunct to immunotherapy for glioblastoma to counteract bevacizumab resistance.

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“…We have previously shown that EMP2 may at least partially serve to increase tumor vascularity through upregulation of VEGF-A within the tumor parenchyma. 22 Resistance to bevacizumab is a well-studied topic, with hypoxia-dependent and hypoxia-independent recruitment of alternative kinase signaling pathways, 29 changes in autophagy, 30 , 31 and upregulation of alternative promotors of angiogenesis 32–38 as potential mechanisms for resistance. Interestingly, in previous gene expression studies in tumors before and after bevacizumab, EMP2 has not been identified as a highly upregulated gene.…”

Section: Discussionmentioning

confidence: 99%

Increased epithelial membrane protein 2 expression in glioblastoma after treatment with bevacizumab

Patel

Kejriwal

Thammachantha

et al. 2020

Neuro-Oncology Advances

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Introduction Anti-angiogenic therapy with bevacizumab has failed to provide substantial gains in overall survival. Epithelial membrane protein 2 (EMP2) is a cell surface protein that has been previously shown to be expressed in glioblastoma, correlate with poor survival, and regulate neoangiogenesis in cell lines. Thus, the relationship of bevacizumab and EMP2 was investigated. Methods Tumor samples were obtained from 12 patients with newly diagnosed glioblastoma at two time points: 1) during the initial surgery and 2) during a subsequent surgery following disease recurrence post bevacizumab treatment. Clinical characteristics and survival data from these patients were collected, and tumor samples were stained for EMP2 expression. The IVY glioblastoma atlas project database was used to evaluate EMP2 expression levels in 270 samples by differing histological areas of tumor. Results Patients with high EMP2 staining at initial diagnosis had decreased progression free and overall survival after bevacizumab [median progression free survival 4.6 months vs. 5.9 months; Log-Rank P = 0.076 & overall survival 7.7 months vs. 14.4 months; Log-Rank P = 0.011]. There was increased EMP2 staining in samples obtained after bevacizumab treatment in both unpaired [Mean H-score 2.31 vs 1.76; P=0.006] and paired analyses [Mean difference 0.571; P=0.019]. This expression increase correlated with length of bevacizumab therapy [R2=0.449; Pearson P=0.024]. Conclusions Bevacizumab treatment increased EMP2 protein expression. This increase in EMP2 correlated with reduced mean survival time post bevacizumab therapy. We hypothesize a role of EMP2 in clinical bevacizumab resistance and as a potential anti-angiogenic therapeutic target in glioblastoma.

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The Role of Kinase Signaling in Resistance to Bevacizumab Therapy for Glioblastoma Multiforme

Cited by 18 publications

References 128 publications

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy

Systematic analysis of potential targets of the curcumin analog pentagamavunon-1 (PGV-1) in overcoming resistance of glioblastoma cells to bevacizumab

Increased epithelial membrane protein 2 expression in glioblastoma after treatment with bevacizumab

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