Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma

Chiesa, S.; Mangraviti, Antonella; Martini, Maurizio; Cenci, Tonia; Mazzarella, Ciro; Gaudino, Simona; Bracci, Serena; Martino, A. Di; Pepa, Giuseppe Maria Della; Offi, Martina; Gessi, Marco; Russo, Rosellina; Martucci, Matia; Bartoli, F. Beghella; Larocca, Luigi Maria; Lauretti, Liverana; Olivi, Alessandro; Pallini, Roberto; Boccadoro, Mario; D’Alessandris, Quintino Giorgio

doi:10.1038/s41598-022-20417-y

Cited by 8 publications

(11 citation statements)

References 21 publications

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“…Santangelo and colleagues [ 12 ] identified five biomarkers which could help in identifying a subpopulation of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Analogously, Chiesa et al [ 47 ] very recently published the results of an NGS study performed on a cohort of 30 GBM patients harboring recurrent glioblastoma and treated with regorafenib. They identified two different mutations which seem to be associated with a poor response to regorafenib: a mutation in the EGFR pathway and a mutation in the mitogen-activated protein-kinase (MAPK) pathway.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Glioblastoma Cells Response to Regorafenib

Mongiardi

Buccarelli

Formato

et al. 2022

Cancers

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Glioblastoma (GBM), the most malignant primary brain tumor in adults. Although not frequent, it has a relevant social impact because the peak incidence coincides with the age of professional maturity. A number of novel treatments have been proposed, yet clinical trials have been disappointing. Recently, a phase II clinical trial (REGOMA) demonstrated that the multikinase inhibitor regorafenib significantly increased the median overall survival (OS) of GBM patients when compared to lomustine-treated patients. On this basis, the National Comprehensive Cancer Network (NCCN) 2020 Guidelines included regorafenib as a preferred regimen in relapsed GBM treatment. Despite the use in GBM patients’ therapy, little is known about the molecular mechanisms governing regorafenib effectiveness on the GBM tumor. Here we report an in vitro characterization of GBM tumor cells’ response to regorafenib, performed both on cell lines and on patient-derived glioma stem cells (GSCs). Overall, regorafenib significantly reduced cell growth of 2D tumor cell cultures and of 3D tumor spheroids. Strikingly, this effect was accompanied by transcriptional regulation of epithelial to mesenchymal transition (EMT) genes and by an increased ability of surviving tumor cells to invade the surrounding matrix. Taken together, our data suggest that regorafenib limits cell growth, however, it might induce an invasive phenotype.

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Section: Discussionmentioning

confidence: 99%

“…It is interesting to note, as a mere speculation, that GSC#83 are EGFRvIII-positive as opposed to GSC#1. In their recent paper, Chiesa and colleagues [ 47 ] identified EGFR pathway mutation as a characteristic associated with poor response to regorafenib in GBM patients.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Glioblastoma Cells Response to Regorafenib

Mongiardi

Buccarelli

Formato

et al. 2022

Cancers

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“…Additional research has identified molecular features correlated with prolonged survival rate in regorafenib-treated GBM patients. These features include EGFR mutations ( Chiesa et al, 2022 ), gene transcripts such as HIF1A and CDKN1A, miRNAs like miR-3607–3p, miR-301a-3p, miR-93–5p ( Santangelo et al, 2021 ), and MAPK pathway mutations that may associate with a poor prognosis ( Chiesa et al, 2022 ). However, limited evidence restricts the scope of individualized dosing of regorafenib, hence, greater evidence is required to increase its widespread acceptance.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of pharmacotherapy for recurrent high-grade glioma: a systematic review and network meta-analysis

Guan

et al. 2023

Front. Pharmacol.

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Objective: To compare the efficacy and safety of treatments for patients with recurrent high-grade gliomas.Methods: Electronic databases including Pubmed, Embase, Cochrane Library and ClinicalTrials.gov were searched for randomized controlled trials (RCT) related to high-grade gliomas. The inclusion of qualified literature and extraction of data were conducted by two independent reviewers. The primary clinical outcome measures of network meta-analysis were overall survival (OS) while progression-free survival (PFS), objective response rate (ORR) and adverse event of grade 3 or higher were secondary measures.Results: 22 eligible trials were included in the systematic review, involving 3423 patients and 30 treatment regimens. Network meta-analysis included 11 treatments of 10 trials for OS and PFS, 10 treatments of 8 trials for ORR, and 8 treatments of 7 trials for adverse event grade 3 or higher. Regorafenib showed significant benefits in terms of OS in paired comparison with several treatments such as bevacizumab (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.21–0.73), bevacizumab plus carboplatin (HR, 0.33; 95%CI, 0.16–0.68), bevacizumab plus dasatinib (HR, 0.44; 95%CI, 0.21–0.93), bevacizumab plus irinotecan (HR, 0.4; 95%CI, 0.21–0.74), bevacizumab plus lomustine (90 mg/m2) (HR, 0.53; 95%CI, 0.33–0.84), bevacizumab plus lomustine (110 mg/m2) (HR, 0.21; 95%CI, 0.06–0.7), bevacizumab plus vorinostat (HR, 0.42; 95%CI, 0.18–0.99), lomustine (HR, 0.5; 95%CI, 0.33–0.76), and nivolumab (HR, 0.38; 95%CI, 0.19–0.73). For PFS, only the hazard ratio between bevacizumab plus vorinostat and bevacizumab plus lomustine (90 mg/m2) was significant (HR,0.51; 95%CI, 0.27–0.95). Lomustine and nivolumab conferred worse ORR. Safety analysis showed fotemustine as the best and bevacizumab plus temozolomide as the worst.Conclusion: The results suggested that regorafenib and bevacizumab plus lomustine (90 mg/m2) provide improvements in terms of survival but may have poor ORR in patients with recurrent high-grade glioma.

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“…Integrated DNA sequencing and copy number analysis have identified potential driver genes, and molecular profiling, as demonstrated by several clinical sequencing efforts, not only provides insights into glioma biology, but also offers multi‐level solutions, including the development of novel small molecule drugs 7,8 . Targeted sequencing is the selection of mostly established cancer genes for targeted sequencing of the disease to facilitate the selection of the most likely responders to certain anticancer drugs 9 . Deep targeted sequencing of tumor samples is becoming increasingly valuable and its application in the clinic deserves further investigation.…”

Section: Introductionmentioning

confidence: 99%

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

Xiao,

Cui,

et al. 2024

CNS Neurosci Ther

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AimsTo investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair‐related genes and the development of chemoresistance in gliomas.MethodsWe conducted a comprehensive analysis of deep‐targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I‐TASSER for homology modeling. We elucidated the functional changes induced by high‐frequency site mutations in these genes and investigated their impact on glioma progression.ResultsThe analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis.ConclusionThe ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.

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Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma

Cited by 8 publications

References 21 publications

Characterization of Glioblastoma Cells Response to Regorafenib

Characterization of Glioblastoma Cells Response to Regorafenib

Efficacy and safety of pharmacotherapy for recurrent high-grade glioma: a systematic review and network meta-analysis

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

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