Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History

Franceschi, Sara; Civita, Prospero; Pasqualetti, Francesco; Lessi, Francesca; Modena, Martina; Barachini, Serena; Morelli, Maria Sole; Santonocito, Orazio; Vannozzi, Riccardo; Pilkington, Geoffrey J.; Ortenzi, Valerio; Naccarato, Antonio Giuseppe; Aretini, Paolo; Mazzanti, Chiara Maria

doi:10.3390/cancers13092044

Cited by 5 publications

(4 citation statements)

References 76 publications

(100 reference statements)

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“…Firstly, regarding the intertumoral heterogeneity, intrinsic diversities between cancer patients within the same organ are well known and thought to be a major reason for poor overall survival. In this line, many studies reported distinct variations of similar tumor types of different patients [ 35 , 36 , 37 ]. While histopathological and oncological classification showed equal tumor grading, genetic characterization revealed a strong molecular heterogeneity with variances in the mutational analysis as well as in copy number alterations of different genes [ 35 ].…”

Section: Cancer and Cancer Stem Cellsmentioning

confidence: 99%

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

et al. 2022

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Among the cell populations existing within a tumor, cancer stem cells are responsible for metastasis formation and chemotherapeutic resistance. In the present review, we focus on the transcription factor NF-κB, which is present in every cell type including cancer stem cells. NF-κB is involved in pro-tumor inflammation by its target gene interleukin 1 (IL1) and can be activated by a feed-forward loop in an IL1-dependent manner. Here, we summarize current strategies targeting NF-κB by chemicals and biologicals within an integrated cancer therapy. Specifically, we start with a tyrosine kinase inhibitor targeting epidermal growth factor (EGF)-receptor-mediated phosphorylation. Furthermore, we summarize current strategies of multiple myeloma treatment involving lenalidomide, bortezomib, and dexamethasone as potential NF-κB inhibitors. Finally, we discuss programmed death-ligand 1 (PD-L1) as an NF-κB target gene and its role in checkpoint therapy. We conclude, that NF-κB inhibition by specific inhibitors of IκB kinase was of no clinical use but inhibition of upstream and downstream targets with drugs or biologicals might be a fruitful way to treat cancer stem cells.

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Section: Cancer and Cancer Stem Cellsmentioning

confidence: 99%

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

et al. 2022

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“…It has been found that [ 21 ], ITGB8 (β8 integrin) expression was elevated in GBM stem cells and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. DCHS1 (dachsous cadherin-related 1) may belong to some canonical cancer molecular pathways in gliomas [ 22 ] and has been selected as a marker gene in glioma prognostic signature [ 23 ]. Additionally, TGFB2 (Transforming Growth Factor Beta 2) has been identified as a predictor of poor treatment outcomes in pediatric diffuse intrinsic pontine glioma [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Molecular Pathways and Associated Genes as Targets to Overcome Radiotherapy Resistance Using a Combination of Radiotherapy and Immunotherapy in Glioma Patients

Zhang,

et al. 2024

IJMS

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Recent mechanistic studies have indicated that combinations of radiotherapy (RT) plus immunotherapy (via CSF-1R inhibition) can serve as a strategy to overcome RT resistance and improve the survival of glioma mice. Given the high mortality rate for glioma, including low-grade glioma (LGG) patients, it is of critical importance to investigate the mechanism of the combination of RT and immunotherapy and further translate the mechanism from mouse studies to improve survival of RT-treated human glioma patients. Using the RNA-seq data from a glioma mouse study, 874 differentially expressed genes (DEGs) between the group of RT-treated mice at glioma recurrence and the group of mice with combination treatment (RT plus CSF-1R inhibition) were translated to the human genome to identify significant molecular pathways using the KEGG enrichment analysis. The enrichment analysis yields statistically significant signaling pathways, including the phosphoinositide 3-kinase (PI3K)/AKT pathway, Hippo pathway, and Notch pathway. Within each pathway, a candidate gene set was selected by Cox regression models as genetic biomarkers for resistance to RT and response to the combination of RT plus immunotherapies. Each Cox model is trained using a cohort of 295 RT-treated LGG patients from The Cancer Genome Atlas (TCGA) database and validated using a cohort of 127 RT-treated LGG patients from the Chinese Glioma Genome Atlas (CGGA) database. A four-DEG signature (ITGB8, COL9A3, TGFB2, JAG1) was identified from the significant genes within the three pathways and yielded the area under time-dependent ROC curve AUC = 0.86 for 5-year survival in the validation set, which indicates that the selected DEGs have strong prognostic value and are potential intervention targets for combination therapies. These findings may facilitate future trial designs for developing combination therapies for glioma patients.

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“…In GB, one of the most aggressive brain tumor, there is an urgent demand for novel therapeutic approaches [12]. Unfortunately, recent clinical trials in this field have yielded disappointing results.…”

Section: Introductionmentioning

confidence: 99%

Preclinical glioma models in neuro-oncology: enhancing translational research

Barachini,

Morelli,

Santonocito

et al. 2023

Current Opinion in Oncology

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Purpose of review Gliomas represent approximately 25% of all primary brain and other central nervous system (CNS) tumors and 81% of malignant tumors. Unfortunately, standard treatment approaches for most CNS cancers have shown limited improvement in patient survival rates. Recent findings The current drug development process has been plagued by high failure rates, leading to a shift towards human disease models in biomedical research. Unfortunately, suitable preclinical models for brain tumors have been lacking, hampering our understanding of tumor initiation processes and the discovery of effective treatments. In this review, we will explore the diverse preclinical models employed in neuro-oncology research and their contributions to translational science. Summary By utilizing a combination of these preclinical models and fostering interdisciplinary collaborations, researchers can deepen their understanding of glioma brain tumors and develop novel therapeutic strategies to combat these devastating diseases. These models offer promising prospects for personalized and efficacious treatments for these challenging malignancies. Although it is unrealistic to fully replicate the complexity of the human body in vitro, the ultimate goal should be to achieve the closest possible resemblance to the clinical context.

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Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History

Cited by 5 publications

References 76 publications

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Identification of Key Molecular Pathways and Associated Genes as Targets to Overcome Radiotherapy Resistance Using a Combination of Radiotherapy and Immunotherapy in Glioma Patients

Preclinical glioma models in neuro-oncology: enhancing translational research

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