Document Detail


EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy.
MedLine Citation:
PMID:  18650488     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor alpha and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.
Authors:
Nikola Holtkamp; Elke Malzer; Jan Zietsch; Ali Fuat Okuducu; Jana Mucha; Christian Mawrin; Victor-F Mautner; Hans-Ulrich Schildhaus; Andreas von Deimling
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-07-23
Journal Detail:
Title:  Neuro-oncology     Volume:  10     ISSN:  1522-8517     ISO Abbreviation:  Neuro-oncology     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-16     Completed Date:  2009-02-20     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  946-57     Citation Subset:  IM    
Affiliation:
Institute of Neuropathology, Charité-Universitätsmedizin Berlin, CVK, Augustenburger Platz 1, D-13353 Berlin, Germany. nikola.holtkamp@charite.de
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / administration & dosage*
Blotting, Western
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Delivery Systems*
Drug Synergism
Epidermal Growth Factor / genetics,  metabolism
Gene Dosage
Genes, p16
Genes, p53
Humans
Immunohistochemistry
Nerve Sheath Neoplasms / genetics*,  metabolism
PTEN Phosphohydrolase / genetics
Polymorphism, Single-Stranded Conformational
Quinazolines / pharmacology
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  genetics*,  metabolism
Receptor, erbB-2 / genetics*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transforming Growth Factor alpha / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antineoplastic Agents; 0/Quinazolines; 0/Transforming Growth Factor alpha; 62229-50-9/Epidermal Growth Factor; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, erbB-2; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; J4T82NDH7E/erlotinib; P188ANX8CK/trastuzumab
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