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

Andrew B. Lassman, Michael R. Rossi, Jeffrey R. Razier, Lauren E. Abrey, Frank S. Lieberman, Chelsea N. Grefe, Kathleen Lamborn, William Pao, Alan H. Shih, John G. Kuhn, Richard Wilson, Norma J. Nowak, John K. Cowell, Lisa M. DeAngelis, Patrick Wen, Mark R. Gilbert, Susan Chang, W. A. Yung, Michael Prados, Eric C. Holland

Research output: Contribution to journalArticle

189 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7841-7850
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number21
DOIs
StatePublished - Nov 1 2005

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Epidermal Growth Factor Receptor
Brain Neoplasms
Glioma
Comparative Genomic Hybridization
Neoplasms
Chromosomes, Human, Pair 22
Chromosomes, Human, Pair 21
Lung
Mutation
Chromosomes, Human, Pair 6
gefitinib
Erlotinib Hydrochloride
Exons
Research Design
Western Blotting
Phosphorylation
Research

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Lassman, Andrew B.; Rossi, Michael R.; Razier, Jeffrey R.; Abrey, Lauren E.; Lieberman, Frank S.; Grefe, Chelsea N.; Lamborn, Kathleen; Pao, William; Shih, Alan H.; Kuhn, John G.; Wilson, Richard; Nowak, Norma J.; Cowell, John K.; DeAngelis, Lisa M.; Wen, Patrick; Gilbert, Mark R.; Chang, Susan; Yung, W. A.; Prados, Michael; Holland, Eric C.

In: Clinical Cancer Research, Vol. 11, No. 21, 01.11.2005, p. 7841-7850.

Research output: Contribution to journalArticle

Lassman, AB, Rossi, MR, Razier, JR, Abrey, LE, Lieberman, FS, Grefe, CN, Lamborn, K, Pao, W, Shih, AH, Kuhn, JG, Wilson, R, Nowak, NJ, Cowell, JK, DeAngelis, LM, Wen, P, Gilbert, MR, Chang, S, Yung, WA, Prados, M & Holland, EC 2005, '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', Clinical Cancer Research, vol. 11, no. 21, pp. 7841-7850. https://doi.org/10.1158/1078-0432.CCR-05-0421
Lassman, Andrew B. ; Rossi, Michael R. ; Razier, Jeffrey R. ; Abrey, Lauren E. ; Lieberman, Frank S. ; Grefe, Chelsea N. ; Lamborn, Kathleen ; Pao, William ; Shih, Alan H. ; Kuhn, John G. ; Wilson, Richard ; Nowak, Norma J. ; Cowell, John K. ; DeAngelis, Lisa M. ; Wen, Patrick ; Gilbert, Mark R. ; Chang, Susan ; Yung, W. A. ; Prados, Michael ; Holland, Eric C. / 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. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 21. pp. 7841-7850.
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AU - Rossi, Michael R.

AU - Razier, Jeffrey R.

AU - Abrey, Lauren E.

AU - Lieberman, Frank S.

AU - Grefe, Chelsea N.

AU - Lamborn, Kathleen

AU - Pao, William

AU - Shih, Alan H.

AU - Kuhn, John G.

AU - Wilson, Richard

AU - Nowak, Norma J.

AU - Cowell, John K.

AU - DeAngelis, Lisa M.

AU - Wen, Patrick

AU - Gilbert, Mark R.

AU - Chang, Susan

AU - Yung, W. A.

AU - Prados, Michael

AU - Holland, Eric C.

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N2 - 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.

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