Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from North American Brain Tumor Consortium trials 01-03 and 00-01 Journal Article
| Authors: | Lassman, A. B.; Rossi, M. R.; Razier, J. R.; Abrey, L. E.; Lieberman, F. S.; Grefe, C. N.; Lamborn, K.; Pao, W.; Shih, A. H.; Kuhn, J. G.; Wilson, R.; Nowak, N. J.; Cowell, J. K.; De Angelis, L. M.; Wen, P.; Gilbert, M. R.; Chang, S.; Yung, W. A.; Prados, M.; Holland, E. C. |
| Article Title: | Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from North American Brain Tumor Consortium trials 01-03 and 00-01 |
| Abstract: | Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre-erlotinib/gefitinib-exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6,21, and 22, represent new targets for further research. © 2005 American Association for Cancer Research. |
| Keywords: | signal transduction; clinical article; controlled study; human tissue; protein expression; protein phosphorylation; treatment outcome; gene mutation; human cell; exon; gene deletion; mutation; exons; clinical trial; disease course; cancer recurrence; erlotinib; antineoplastic agents; brain tumor; glioma; brain neoplasms; controlled clinical trial; phase 2 clinical trial; cluster analysis; models, biological; lung neoplasms; epidermal growth factor receptor; in vivo study; receptor, epidermal growth factor; antineoplastic activity; time factors; protein kinase inhibitors; lung tumor; blotting, western; gene expression regulation, neoplastic; disease progression; multicenter study; glioblastoma; western blotting; gefitinib; medical society; genome; phase 1 clinical trial; nucleic acid hybridization; quinazolines; comparative genomic hybridization; chromosome 21; chromosome 6; clinical trials; epidermal growth factor receptor kinase inhibitor; sequence analysis, dna; chromosome 22; disease activity |
| Journal Title: | Clinical Cancer Research |
| Volume: | 11 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-11-01 |
| Start Page: | 7841 |
| End Page: | 7850 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-05-0421 |
| PUBMED: | 16278407 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 120" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus" |
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