Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma.

ABSTRACT:

Purpose

Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world.

Methods

EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography.

Results

EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases).

Conclusions

EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.

SUBMITTER: Lassman AB

PROVIDER: S-EPMC8082754 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

ACTR-13. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFICATION RATES OBSERVED IN SCREENING PATIENTS FOR RANDOMIZED CLINICAL TRIALS IN GLIOBLASTOMA

Project description:Abstract BACKGROUND EGFR is a key oncogenic target for the treatment of glioblastoma. EGFR amplification is detected in ~50% of tumors. Depatuxizumab mafodotin (depatux-m), formerly called ABT-414, is a tumor-specific antibody-drug conjugate that preferentially targets tumors with EGFR amplification. Herein, we report the frequency of EGFR amplification in 2 large-scale glioblastoma clinical trials of depatux-m. METHODS As of May 1, 2017, testing for EGFR amplification status was performed centrally in 2077 glioblastoma samples during screening for 2 randomized glioblastoma trials with depatux-m: INTELLANCE 1 (NCT02573324) for newly diagnosed patients (n=1001), and INTELLANCE 2 (NCT02343406) for recurrent disease (n=1076). EGFR amplification, required for eligibility in both trials, was determined by fluorescence in situ hybridization and defined as at least 2 copies in at least 15% of cells. EGFRvIII mutation data will be reported at the meeting. RESULTS Out of 2077 total patients, 1084 were positive for EGFR amplification (52.2%), similar to published rates. Per world region number and frequency of EGFR amplification was as follows: Africa (4/9; 44.4%), Americas (238/451; 52.8%), Asia (69/201; 34.3%), Europe (672/1190; 56.5%), Middle East (21/40; 52.5%), Oceania (80/186; 43.0). CONCLUSIONS To our knowledge, this study represents the first report of lower EGFR amplification rates in patients from Asia with glioblastoma. This observation requires further study.

| S-EPMC5693085 | biostudies-literature

Epidermal growth factor receptor in glioblastoma.

Project description:Mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in glioblastoma. Enhanced activation of EGFR can occur through a variety of different mechanisms, both ligand-dependent and ligand-independent. Numerous evidence has suggested that EGFR is overexpressed in most of primary glioblastomas and some of the secondary glioblastomas and is characteristic of more aggressive glioblastoma phenotypes. Additionally, recent studies have revealed that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants induced a substantial upregulation of Fyn expression. Furthermore, it was determined that Fyn expression is upregulated across a panel of patient-derived glioblastoma stem cells (GSCs) relative to normal progenitor controls. Moreover, researchers are continuously involved in elucidation of novel mechanism linking EGFR EGFR-expressing glioblastoma. The present review highlights current aspects of EGFR receptor in glioblastoma and concludes that the concept of EGFR signaling and related receptors and associated factors is evolving, however, it needs detailed evaluation for future clinical applications in cancer patients.

| S-EPMC5494611 | biostudies-other

Screening and discovery of nitro-benzoxadiazole compounds activating epidermal growth factor receptor (EGFR) in cancer cells.

Project description:Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other receptor tyrosine kinases in cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in cancer cells exposed to electrophilic NBD compounds.

| S-EPMC3913914 | biostudies-literature

Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma.

Project description:Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM.

| S-EPMC5053413 | biostudies-literature

Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling.

Project description:Glioblastoma multiforme is a deadly cancer for which current treatment options are limited. The ability of glioblastoma tumor cells to infiltrate the surrounding brain parenchyma critically limits the effectiveness of current treatments. We investigated how microglia, the resident macrophages of the brain, stimulate glioblastoma cell invasion. We first examined the ability of normal microglia from C57Bl/6J mice to stimulate GL261 glioblastoma cell invasion in vitro. We found that microglia stimulate the invasion of GL261 glioblastoma cells by approximately eightfold in an in vitro invasion assay. Pharmacological inhibition of epidermal growth factor receptor (EGFR) strongly inhibited microglia-stimulated invasion. Furthermore, blockade of colony stimulating factor 1 receptor (CSF-1R) signaling using ribonucleic acid (RNA) interference or pharmacological inhibitors completely inhibited microglial enhancement of glioblastoma invasion. GL261 cells were found to constitutively secrete CSF-1, the levels of which were unaffected by epidermal growth factor (EGF) stimulation, EGFR inhibition or coculture with microglia. CSF-1 only stimulated microglia invasion, whereas EGF only stimulated glioblastoma cell migration, demonstrating a synergistic interaction between these two cell types. Finally, using PLX3397 (a CSF-1R inhibitor that can cross the blood-brain barrier) in live animals, we discovered that blockade of CSF-1R signaling in vivo reduced the number of tumor-associated microglia and glioblastoma invasion. These data indicate that glioblastoma and microglia interactions mediated by EGF and CSF-1 can enhance glioblastoma invasion and demonstrate the possibility of inhibiting glioblastoma invasion by targeting glioblastoma-associated microglia via inhibition of the CSF-1R.

| S-EPMC3356419 | biostudies-other

Glioblastoma-derived epidermal growth factor receptor carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies.

Project description:Genomic alterations of the epidermal growth factor receptor (EGFR) gene play a crucial role in pathogenesis of glioblastoma multiforme (GBM). By systematic analysis of GBM genomic data, we have identified and characterized a novel exon 27 deletion mutation occurring within the EGFR carboxyl-terminus domain (CTD), in addition to identifying additional examples of previously reported deletion mutations in this region. We show that the GBM-derived EGFR CTD deletion mutants are able to induce cellular transformation in vitro and in vivo in the absence of ligand and receptor autophosphorylation. Treatment with the EGFR-targeted monoclonal antibody, cetuximab, or the small molecule EGFR inhibitor, erlotinib, effectively impaired tumorigenicity of oncogenic EGFR CTD deletion mutants. Cetuximab in particular prolonged the survival of intracranially xenografted mice with oncogenic EGFR CTD deletion mutants, compared with untreated control mice. Therefore, we propose that erlotinib and, especially, cetuximab treatment may be a promising therapeutic strategy in GBM patients harboring EGFR CTD deletion mutants.

| S-EPMC3242822 | biostudies-literature

Quantitative proteomic analysis reveals effects of epidermal growth factor receptor (EGFR) on invasion-promoting proteins secreted by glioblastoma cells.

Project description:Glioblastoma multiforme is a highly invasive and aggressive brain tumor with an invariably poor prognosis. The overexpression of epidermal growth factor receptor (EGFR) is a primary influencer of invasion and proliferation in tumor cells and the constitutively active EGFRvIII mutant, found in 30-65% of Glioblastoma multiforme, confers more aggressive invasion. To better understand how EGFR contributes to tumor aggressiveness, we investigated the effect of EGFR on the secreted levels of 65 rationally selected proteins involved in invasion. We employed selected reaction monitoring targeted mass spectrometry using stable isotope labeled internal peptide standards to quantity proteins in the secretome from five GBM (U87) isogenic cell lines in which EGFR, EGFRvIII, and/or PTEN were expressed. Our results show that cell lines with EGFR overexpression and constitutive EGFRvIII expression differ remarkably in the expression profiles for both secreted and intracellular signaling proteins, and alterations in EGFR signaling result in reproducible changes in concentrations of secreted proteins. Furthermore, the EGFRvIII-expressing mutant cell line secretes the majority of the selected invasion-promoting proteins at higher levels than other cell lines tested. Additionally, the intracellular and extracellular protein measurements indicate elevated oxidative stress in the EGFRvIII-expressing cell line. In conclusion, the results of our study demonstrate that EGFR signaling has a significant effect on the levels of secreted invasion-promoting proteins, likely contributing to the aggressiveness of Glioblastoma multiforme. Further characterization of these proteins may provide candidates for new therapeutic strategies and targets as well as biomarkers for this aggressive disease.

| S-EPMC4188991 | biostudies-literature

Targeting Epidermal Growth Factor Receptor (EGFR) in Pediatric Colorectal Cancer.

Project description:Background: Colorectal carcinoma (CRC) is very rare in the pediatric and adolescent age range and clinical management is performed according to adult protocols. We report, for the first time in the literature, a case of a child with metastatic CRC successfully treated with panitumumab associated to chemotherapy. Methods: A twelve-year-old male was diagnosed with CRC with nodal metastasis and peritoneal neoplastic effusion. After performing a genetic evaluation, in light of the absence of mutations in RAS family genes, anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody, panitumumab, was added to chemotherapy FOLFOXIRI. Results: The child successfully responded to therapy with normalization of the Carbohydrate Antigen (CA) 19.9 value after the third cycle of treatment. After the sixth cycle, he underwent surgery that consisted in sigmoid resection with complete D3 lymphadenectomy. At histological evaluation, no residual neoplastic cells were detectable in the surgical specimen. He completed 12 cycles of chemotherapy plus panitumomab and he is alive without disease 14 months from diagnosis. Conclusions: Our results suggest performing mutational screening for colorectal cancer also in the pediatric setting, in order to orient treatment that should include targeted therapies.

| S-EPMC7072611 | biostudies-literature

EGFR Amplification and Glioblastoma Stem-Like Cells.

Project description:Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintained in vitro using serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retained EGFR amplification could overcome the limitations of current in vitro model systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with different EGFR status in order to maintain EGFR-dependent intratumoral heterogeneity in vitro. Further, it will summarize the current knowledge about the impact of EGFR amplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM.

| S-EPMC4468289 | biostudies-other

Epidermal Growth Factor Receptor (EGFR) Antagonist Chimeric Anti-EGFR Monoclonal Antibody Trial

Project description:The study is an double blind, randomized, multicenter phase 3 trial. The efficacy analyses are based on 570 Chinese patients with RAS wt mCRC treated with mFOLFOX-6 ± cetuximab. Study treatment continues until disease progression or unacceptable toxicity (ie, not for a fixed number of courses). The primary endpoint of the study is progression-free survival (PFS) time according to RECIST 1.0; key secondary endpoints include overall survival (OS) time, overall response rate (ORR), and safety/tolerability.

| 2265349 | ecrin-mdr-crc

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data