Amplification of the Epidermal Growth Factor Receptor gene (EGFR) represents the most common oncogene activation event in glioblastoma, the most common and malignant form of brain tumor. In the vast majority of glioblastomas, EGFR amplification is accompanied by EGFR mutation. Little is known, however, about the functional and biologic consequences of the mutations that have been identified. Understanding these consequences is important because many of the therapies that are under consideration for the treatment of cancer patients rely upon the effects of inhibitors intended to block the function of receptor tyrosine kinases such as EGFR, or the signaling proteins downstream of these receptors. Here we propose to initiate a systematic analysis of mutant EGF receptors known to be expressed in human glioblastomas. This analysis will be accompanied by studies examining the effects of chemical inhibitors, as well as dominant-negative proteins, on wild type and mutant EGF receptor signaling, and will include a collaborative investigation with Dr. Allan Yates (Project 4) to examine the effects of an endogenous glycolipid, GM3, on EGF receptor function. The project also contains a clinical translational component that will determine whether EGFR amplification, amplification level, and/or specific types of EGFR mutations confer a particularly poor prognosis for subsets of malignant glioma patients. In total it is anticipated that the information obtained through the implementation of this project will lead to an improved understanding of EGF receptor structure-function relationships, and an ability to exploit this understanding for the treatment of patients afflicted with this cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA085799-01A1
Application #
6487994
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2001-06-14
Project End
2005-05-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Phillips, Joanna J; Misra, Anjan; Feuerstein, Burt G et al. (2010) Pituicytoma: characterization of a unique neoplasm by histology, immunohistochemistry, ultrastructure, and array-based comparative genomic hybridization. Arch Pathol Lab Med 134:1063-9
Jenkins, Robert B; Blair, Hilary; Ballman, Karla V et al. (2006) A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66:9852-61
Omran, O M; Saqr, H E; Yates, Allan J (2006) Molecular mechanisms of GD3-induced apoptosis in U-1242 MG glioma cells. Neurochem Res 31:1171-80
Saqr, H E; Omran, O; Dasgupta, S et al. (2006) Endogenous GD3 ganglioside induces apoptosis in U-1242 MG glioma cells. J Neurochem 96:1301-14
Saqr, H E; Omran, O M; Oblinger, J L et al. (2006) TRAIL-induced apoptosis in U-1242 MG glioma cells. J Neuropathol Exp Neurol 65:152-61
Oblinger, J L; Pearl, D K; Boardman, C L et al. (2006) Diagnostic and prognostic value of glycosyltransferase mRNA in glioblastoma multiforme patients. Neuropathol Appl Neurobiol 32:410-8
Misra, Anjan; Pellarin, Malgorzata; Hu, Lily et al. (2006) Chromosome transfer experiments link regions on chromosome 7 to radiation resistance in human glioblastoma multiforme. Genes Chromosomes Cancer 45:20-30
Nigro, Janice M; Misra, Anjan; Zhang, Li et al. (2005) Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res 65:1678-86
Misra, Anjan; Pellarin, Malgorzata; Nigro, Janice et al. (2005) Array comparative genomic hybridization identifies genetic subgroups in grade 4 human astrocytoma. Clin Cancer Res 11:2907-18
Law, Mark E; Templeton, Kristen L; Kitange, Gaspar et al. (2005) Molecular cytogenetic analysis of chromosomes 1 and 19 in glioma cell lines. Cancer Genet Cytogenet 160:1-14

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