The long term goal of this laboratory is to determine the molecular basis of the cytogenetic abnormalities which characterize human gliomas and to define the role of these alterations in the genesis and progression of these tumors. During the previous funding period, we have determined that loss of heterozygosity (LOH) for 17p is associated with the TP53 gene mutations, that double minute chromosomes (DMs) are associated with amplification, often with rearrangement, of the epidermal growth factor receptor (EGFR) gene, that loss of 9p is associated with homozygous deletion of the CDKN2 gene, and that loss of all or part of chromosome 10 often reflects deletion or mutation of the PTEN/MMAC1 gene. In the present application we will use these genetic alterations, along with histologic parameters and immunohistochemical markers, to precisely and reproducibly separate glioma patients into prognostic groups and to identify patients who are likely to respond to specific forms of treatment.
In Specific Aim 1 we will test the ability of age of the patient, histologic features, proliferation index, p53 gene mutations, gene amplification, and LOH for 1p, 9p, chromosome 10, and 19q to distinguish between astrocytic and oligodendroglial tumors and to grade tumors within these cytologic groups. We will also use immunohistochemical and biochemical markers to identify patients whose tumors contain antigens or molecular defects which render them susceptible or resistant to specific therapeutic modalities. Since loss of chromosome 10 tumor suppressor genes which are altered in these tumors, including PTEN, DMBT1, and new suppressor genes, particularly on 10p. We believe that these studies will provide accurate classification of brain tumor patients, for the prospective analysis of specific therapeutic regimens. Our goal is to select therapy for individual patients based on immunohistochemical, biochemical, or molecular genetic characteristics of their tumors, and by doing so have the best chance of avoiding resistance and achieving response or even cure in a subset of malignant glioma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043722-15
Application #
6341897
Study Section
Special Emphasis Panel (ZRG2-MEP (03))
Program Officer
Lively, Tracy (LUGO)
Project Start
1987-01-01
Project End
2003-12-31
Budget Start
2001-01-08
Budget End
2001-12-31
Support Year
15
Fiscal Year
2001
Total Cost
$333,231
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
McLendon, Roger E; Herndon 2nd, James E; West, Bryan et al. (2005) Survival analysis of presumptive prognostic markers among oligodendrogliomas. Cancer 104:1693-9
Rasheed, B K; McLendon, R E; Herndon, J E et al. (1994) Alterations of the TP53 gene in human gliomas. Cancer Res 54:1324-30
Fuller, G N; Bigner, S H (1992) Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res 276:299-306
Rasheed, B K; Fuller, G N; Friedman, A H et al. (1992) Loss of heterozygosity for 10q loci in human gliomas. Genes Chromosomes Cancer 5:75-82
Fuchs, H E; Archer, G E; Colvin, O M et al. (1990) Activity of intrathecal 4-hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis. Cancer Res 50:1954-9
Bigner, S H; Mark, J; Bigner, D D (1990) Cytogenetics of human brain tumors. Cancer Genet Cytogenet 47:141-54
Fredman, P; Mansson, J E; Bigner, S H et al. (1990) Gangliosides in the human glioma cell line U-118 MG grown in culture or as xenografts in nude rats. Biochim Biophys Acta 1045:239-44
Bigner, S H (1990) Molecular probes in neuro-oncology: the future. Cancer Invest 8:445-6
Bigner, S H; Schold, S C; Friedman, H S et al. (1989) Chromosomal composition of malignant human gliomas through serial subcutaneous transplantation in athymic mice. Cancer Genet Cytogenet 40:111-20
Rosenberg, M C; Colvin, O M; Griffith, O W et al. (1989) Establishment of a melphalan-resistant rhabdomyosarcoma xenograft with cross-resistance to vincristine and enhanced sensitivity following buthionine sulfoximine-mediated glutathione depletion. Cancer Res 49:6917-22

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