Amplified cellular oncogenes in neoplasms of the human central nervous system

Fuller, Gregory N.; Bigner, Sandra H.

doi:10.1016/0165-1110(92)90016-3

Cited by 116 publications

(52 citation statements)

References 27 publications

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“…EGFR is overexpressed in approximately 50% of primary GBM patients (28) and the high prevalence of EGFRvIII in GBM (25%-35%) is well established (29). GBM patients generally have a very poor prognosis, making EGFR an attractive therapeutic target in this indication.…”

Section: Discussionmentioning

confidence: 99%

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Reilly

Phillips

Buchanan

et al. 2015

Molecular Cancer Therapeutics

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Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indiumlabeled version of ABT-806, [ 111 In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIIIexpressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.

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Section: Discussionmentioning

confidence: 99%

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Reilly

Phillips

Buchanan

et al. 2015

Molecular Cancer Therapeutics

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“…Amplifications have rarely been reported in medulloblastomas, usually as double minutes. When analysed, the target genes of these amplifications were either MYC, MYCN or EGFR (Rouah et al, 1989;Wasson et al, 1990;Fuller and Bigner, 1992), and more recently the 5p15 and 11q22 regions (Reardon et al, 1997). None of these regions was amplified in our series.…”

Section: Discussionmentioning

confidence: 99%

“…Other recurrent abnormalities have been described, including structural aberrations of chromosomes 1, 3, 6, 11, 16 and X, loss of chromosome 22 and gains of chromosomes 6 and 8 (Farwell et al, 1977;Bigner et al, 1988Bigner et al, , 1990Griffin et al, 1988;Callen et al, 1989;Karnes et al, 1992;Neumann et al, 1993;Fujii et al, 1994). Few gene amplifications have been reported, involving MYC, MYCN or EGFR (Rouah et al, 1989;Wasson et al, 1990;Fuller and Bigner, 1992;Badiali et al, 1995), and more recently the 5p15 and 11q22 chromosomal regions (Reardon et al, 1997).…”

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confidence: 99%

Comparative genomic hybridization detects many recurrent imbalances in central nervous system primitive neuroectodermal tumours in children

Avet-Loiseau¹,

et al. 1999

Br J Cancer

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Summary A series of 23 children with primitive neuroectodermal tumours (PNET) were analysed with comparative genomic hybridization (CGH). Multiple chromosomal imbalances have been detected in 20 patients. The most frequently involved chromosome was chromosome 17, with a gain of 17q (11 cases) and loss of 17p (eight cases). Further recurrent copy number changes were detected. Extra copies of chromosome 7 were present in nine patients and gains of 1q were detected in six patients. A moderate genomic amplification was detected in one patient, involving two sites on 3p and the whole 12p. Losses were more frequent, and especially involved the chromosomes 11 (nine cases), 10q (eight cases), 8 (six cases), X (six patients) and 3 (five cases), and part of chromosome 9 (five cases). These recurrent chromosomal changes may highlight locations of novel genes with an important role in the development and/or progression of PNET.

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“…8 EGFR is a well-established treatment target for colorectal cancer, non-small cell lung cancer, and squamous cell carcinoma of the head and neck. In breast cancer, EGFR overexpression has been reported in up to 78% of triple-negative breast cancers, [9][10][11][12][13][14][15][16][17][18][19][20] more than in non-triple-negative breast cancers, 12,15 suggesting that EGFR is a potential therapeutic target for triple-negative breast cancer.…”

Section: Introductionmentioning

confidence: 99%

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

Park¹,

et al. 2014

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Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n ¼ 1), V786M in exon 20 (n ¼ 1), and L858R in exon 21 (n ¼ 3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

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Amplified cellular oncogenes in neoplasms of the human central nervous system

Cited by 116 publications

References 27 publications

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Comparative genomic hybridization detects many recurrent imbalances in central nervous system primitive neuroectodermal tumours in children

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

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