Targeting the RhoGEF βPIX/COOL-1 in Glioblastoma: Proof of Concept Studies

Connor, Kate; Murray, David; Jarzabek, Monika A.; Tran, Nhan L.; White, Kieron; Sweeney, Kieron; O'Halloran, Philip J; MacCarthy, Brian; Shiels, Liam; Lodi, Francesca; Lambrechts, Diether; Sarkaria, Jann N.; Schiffelers, Raymond M.; Symons, Marc; Byrne, Annette T.

doi:10.3390/cancers12123531

Cited by 5 publications

(3 citation statements)

References 63 publications

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“…ARHGEF7 (Rho guanine nucleotide exchange factor 7) belongs to Ras-like family of Rho proteins and has an important role during neuronal development [ 11 ]. Upregulation of ARHGEF7, also known as βPix (Pax-interacting exchange factor beta) or Cool1 (Cloned out of library 1), might play a key role in glioblastoma cell invasion [ 12 ].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Larotrectinib Response in NTRK3 Fusion-Driven Diffuse High-Grade Glioma

König¹,

Hench²,

Frank³

et al. 2022

Pharmacology

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High-grade glioma (HGG) and glioblastoma are the most common adult malignant brain tumors. The standard treatment consists of surgical resection followed by radiochemotherapy with temozolomide. The prognosis and the therapeutic options of these malignant brain tumors however are limited. Here, we describe a case of a patient with HGG with a previously unknown NTRK3 fusion that showed an extraordinary response to treatment with larotrectinib. This case supports regular testing for NTRK fusion proteins.

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Section: Discussion/conclusionmentioning

confidence: 99%

Larotrectinib Response in NTRK3 Fusion-Driven Diffuse High-Grade Glioma

König¹,

Hench²,

Frank³

et al. 2022

Pharmacology

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“…We found discordant changes in the expression of a few genes including ARHGEF7, OLFM1, PPP1R16B, and IFI16, while other were shown to be altered in GBM samples compared to normal controls in concordant to the past ndings in other studies ( Table 1).All of the genes in the signature except for ARHGEF7 with less changes but also signi cant showed highly signi cant alterations in their expression levels compared to control samples. Among them, ARHGEF7 (also called beta Pix or Cool1) encodes a guanine-nucleotide exchange factor (GEF) has been found to be upregulated in glioblastoma cell lines playing an essential role in the tumorigenesis of invasive cells and its knockdown was revealed to reverse the promoting impacts on tumor cell proliferation and invasion (30). Methylation status of ARHGEF7 has been studied in several cell types of GBM and in combination with others is suggested as a signature in classi cation, prognosis and treatment of GBM disease (31).…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of Dna Methylation and Gene Expression Profiles to Explore Potential Biomarkers of Glioblastoma

Rahmati

Najafi

Alivand

2021

Preprint

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Glioblastoma multiform (GBM) is the most common, most invasive, and malignant type of primary brain tumor with poorly prognosis and poorly survival rate. Using GSE22891 the expression and methylation status of same GBM patients was evaluated to explore key epigenetic genes in GBM. Using |log2FC| > 1 and FDR < 0.05 as the threshold, DEGs including 4910 downregulated and 2478 upregulated were screened and by |log2FC| > 0.2 and p.value < 0.05, 3223 DMCs were detected. By merging the results of DEGs and DMCs, 643 genes were selected for network analysis by WGCNA, and based on expression values three modules and by methylation values, one module was selected. Using STRING and Cytoscape, PPI network of genes of all modules were constructed separately. According to the PPI network, core genes were picked out. The expression status of core genes was evaluated using GSE77043, GSE42656, GSE30563, GSE22891, GSE15824, and GSE122498, and 50 genes were validated. The methylation status of 50 genes was explored using GSE50923, GSE22891, and GSE36245, and finally, 12 hub genes including ARHGEF7, RAB11FIP4, PPP1R16B, OLFM1, CLDN10, BCAT1, C1QB, C1QC, IFI16, NUP37, PARP9, and PCALF were selected. Using GEPIA database, the expression and survival plot, and using cBioportal the scatterplot of methylation versus expression of 12 hub genes were extracted based on TCGA. To determine the diagnostic values of the hub genes, the ROC curve and the area under the curve (AUC) were extracted based on GSE22891.

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“…The invasive 24,39 human GBM cell line U87R-Luc2 (gift from Peter Forsyth, Moffitt Cancer Center, Tampa, FL) was cultured in Dulbecco's Modified Eagle's Medium (DMEM) F12 supplemented with 10% fetal bovine serum and 400 mg/mL G418 22 .…”

Section: Cell Culturementioning

confidence: 99%

A clinically relevant computed tomography (CT) radiomics strategy for intracranial rodent brain tumour monitoring

Connor,

Conroy,

White

et al. 2024

Sci Rep

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Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. ‘glszm Zone Entropy’), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical ‘discovery’ radiomics in the neuro-oncology space.

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Targeting the RhoGEF βPIX/COOL-1 in Glioblastoma: Proof of Concept Studies

Cited by 5 publications

References 63 publications

Larotrectinib Response in NTRK3 Fusion-Driven Diffuse High-Grade Glioma

Larotrectinib Response in NTRK3 Fusion-Driven Diffuse High-Grade Glioma

Integrative Analysis of Dna Methylation and Gene Expression Profiles to Explore Potential Biomarkers of Glioblastoma

A clinically relevant computed tomography (CT) radiomics strategy for intracranial rodent brain tumour monitoring

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