Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches

Alexandru, Oana; Horescu, Cristina; Sevastre, Ani-Simona; Cioc, Cătălina Elena; Baloi, Carina; Opriţa, Alexandru; Dricu, Anica

doi:10.5114/wo.2020.94726

Cited by 32 publications

(34 citation statements)

References 148 publications

(136 reference statements)

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“…Another chromatin remodeler, H3F3A , whose driver mutations HK27M and G34R induce dysfunction of Polycomb repressive complex 2 ( PRC2 ) and dramatic alterations of gene expression (21, 22), may contribute to high alterations in profile expression for mesenchymal GBM subtype. EGFR , which is perhaps one of the best-characterized molecules in primary GBM (23), showed a down-regulation in mesenchymal and proneural subtypes, but a clear up-regulation in the classical GBM subtype. This behavior is conserved across all age groups and strikingly marked for the elderly population.…”

Section: Discussionmentioning

confidence: 99%

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Glioblastoma Multiforme: A Meta-Analysis of Driver Genes, Current Diagnosis, and Tumor Heterogeneity

Herrera-Oropeza¹,

Angulo-Rojo²,

Gástelum-López³

et al. 2020

Preprint

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Glioblastoma (GBM) is the most aggressive and common brain cancer in adults with the lowest life expectancy. The current neuro-oncology practice has incorporated genes involved in key molecular events that drive GBM tumorigenesis as biomarkers to guide diagnosis and design treatment. This study summarizes findings describing the significant heterogeneity of GBM at the transcriptional and genomic levels, emphasizing eighteen driver genes with clinical relevance. A pattern was identified fitting the stem cell model for GBM ontogenesis, with an up-regulation profile for MGMT and down-regulation for ATRX, H3F3A, TP53, and EGFR in the mesenchymal subtype. We also detected overexpression of EGFR, NES, VIM, and TP53 in the classical subtype and of MKi67 and OLIG2 genes in the proneural subtype. In keeping with this, we found a combination of eight biomarkers with a strong potential to determine the GBM molecular subtype. A unique distribution of somatic mutations was found for the young and adult population, particularly for genes related to DNA repair and chromatin remodeling, highlighting ATRX, MGMT, and IDH1. Our results also revealed that highly lesioned genes undergo differential regulation with particular biological pathways for young patients. This meta-analysis will help delineate future strategies related to the use of these molecular markers for clinical decision-making in the medical routine.

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Section: Discussionmentioning

confidence: 99%

“…The SMARCB1 22q11 23. gene encodes a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex.…”

mentioning

confidence: 99%

Glioblastoma Multiforme: A Meta-Analysis of Driver Genes, Current Diagnosis, and Tumor Heterogeneity

Herrera-Oropeza¹,

Angulo-Rojo²,

Gástelum-López³

et al. 2020

Preprint

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“…Based on the expression patterns’ differences, glioblastomas are divided into three subtypes as follows: classical, proneural, and mesenchymal [ 2 ]. Because glioblastoma multiforme (GBM), a grade IV glioma [ 3 ], is one of the most aggressive primary brain tumors, recent studies and reviews have focused on deepening our understanding of the disease [ 4 , 5 , 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Updated Insights on EGFR Signaling Pathways in Glioma

Opriţa

Baloi

Staicu

et al. 2021

IJMS

Self Cite

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Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

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“…In December 2019, a trial involving BGJ398 in rGBM was completed, but no results have been published yet. Another phase I/II trial using TAS-120 is currently recruiting patients with metastatic solid tumours, regardless of fibroblast growth factor (FGF)/FGFR-related abnormalities [67].…”

Section: Fibroblast Growth Factor Receptor (Fgfr)mentioning

confidence: 99%

Therapeutic strategies of recurrent glioblastoma and its molecular pathways ‘Lock up the beast’

El-Khayat

Arafat

2021

ecancer

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Glioblastoma multiforme (GBM) has a poor prognosis-despite aggressive primary treatment composed of surgery, radiotherapy and chemotherapy, median survival is still around 15 months. It starts to grow again after a year of treatment and eventually nothing is effective at this stage. Recurrent GBM is one of the most disappointing fields for researchers in which their efforts have gained no benefit for patients. They were directed for a long time towards understanding the molecular basis that leads to the development of GBM. It is now known that GBM is a heterogeneous disease and resistance comes mainly from the regrowth of malignant cells after eradicating specific clones by targeted treatment. Epidermal growth factor receptor, platelet derived growth factor receptor, vascular endothelial growth factor receptor are known to be highly active in primary and recurrent GBM through different underlying pathways, despite this bevacizumab is the only Food and Drug Administration (FDA) approved drug for recurrent GBM. Immunotherapy is another important promising modality of treatment of GBM, after proper understanding of the microenvironment of the tumour and overcoming the reasons that historically stigmatise GBM as an 'immunologically cold tumour'. Radiotherapy can augment the effect of immunotherapy by different mechanisms. Also, dual immunotherapy which targets immune pathways at different stages and through different receptors further enhances immune stimulation against GBM. Delivery of pro-drugs to be activated at the tumour site and suicidal genes by gene therapy using different vectors shows promising results. Despite using neurotropic viral vectors specifically targeting glial cells (which are the cells of origin of GBM), no significant improvement of overall-survival has been seen as yet. Non-viral vectors 'polymeric and non-polymeric' show significant tumour shrinkage in pre-clinical trials and now at early-stage clinical trials. To this end, in this review, we aim to study the possible role of different molecular pathways that are involved in GBM's recurrence, we will also review the most relevant and recent clinical experience with targeted treatments and immunotherapies. We will discuss trials utilised tyrosine receptor kinase inhibitors, immunotherapy and gene therapy in recurrent GBM pointing to the causes of potential disappointing preliminary results of some of them. Additionally, we are suggesting a possible future treatment based on recent successful clinical data that could alter the outcome for GBM patients.

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Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches

Cited by 32 publications

References 148 publications

Glioblastoma Multiforme: A Meta-Analysis of Driver Genes, Current Diagnosis, and Tumor Heterogeneity

Glioblastoma Multiforme: A Meta-Analysis of Driver Genes, Current Diagnosis, and Tumor Heterogeneity

Updated Insights on EGFR Signaling Pathways in Glioma

Therapeutic strategies of recurrent glioblastoma and its molecular pathways ‘Lock up the beast’

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