The long-term goals of this research are to understand the molecular mechanisms of growth regulation and tumor progression in human gliomas. Recent data have suggested that TGF-a and the EGF receptor represent a major autocrine growth regulatory loop in human gliomas while VEGF could be the predominant angiogenic growth factor secreted by glioma cells. In the next five years it is planned to focus on the modulation of these three factors and receptor as a basis for future molecular therapy of malignant gliomas in the clinic. The hypotheses to be tested are: 1) amplification of and over-expression of EGFR/TGF-a and VEGF correlate with malignant progression from astrocytoma to glioblastoma, and 2) modulation of these factors will provide an inhibitory effect to the progression and growth of human glioblastoma.
The specific aims are to 1) determine the expression and alteration of EGF-R, TGF-a, and VEGF in glioma and brain adjacent to tumor. This will be accomplished by PCR, in situ hybridization, and immunohistochemical methods. 2) Triple helix forming oligonucleotides will be designed to inhibit transcription through the promoter region of EGF-R and VEGF genes. Chemical modifications will also be applied to increase the binding efficiency and uptake of these oligonucleotides. 3) To modulate the expression of EGF-R and VEGF using these TFOs. Cells will be tested for growth inhibition, inhibition of transcription by PCR, RNA protection assay and Northern blot; protein synthesis will be determined by receptor binding, Western blot and immunokinase assays. In vivo activity will be determined with nude mice xenografts both subcutaneously and intracranially. 4) To modulate the activity of TGF-a by antisense oligonucleotides and antisense vectors. The biological activities of antisense TGF-a vectors and oligonucleotides will be further investigated. Any synergistic activity between antisense oligonucleotides and TFO's will also be focused upon.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG3-ET-1 (02))
Program Officer
Freeman, Colette S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
Zip Code
Cerrato, Julie A; Khan, Tahira; Koul, Dimpy et al. (2004) Differential activation of the Fas/CD95 pathway by Ad-p53 in human gliomas. Int J Oncol 24:409-17
Ke, Li Dao; Shi, Yue-Xi; Yung, W K Alfred (2002) VEGF(121), VEGF(165) overexpression enhances tumorigenicity in U251 MG but not in NG-1 glioma cells. Cancer Res 62:1854-61
Koul, Dimpy; Jasser, Samar A; Lu, Yiling et al. (2002) Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene 21:2357-64
Koul, D; Parthasarathy, R; Shen, R et al. (2001) Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20:6669-78
Cerrato, J A; Yung, W K; Liu, T J (2001) Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis. Neuro Oncol 3:113-22
Glass, T L; Liu, T J; Yung, W K (2000) Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336. Neuro Oncol 2:151-8
Ke, L D; Chen, Z; Yung, W K (2000) A reliability test of standard-based quantitative PCR: exogenous vs endogenous standards. Mol Cell Probes 14:127-35
Ke, L D; Shi, Y X; Im, S A et al. (2000) The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin Cancer Res 6:2562-72
Tang, P; Jasser, S A; Sung, J C et al. (1999) Transforming growth factor-alpha antisense vectors can inhibit glioma cell growth. J Neurooncol 43:127-35
Sano, T; Lin, H; Chen, X et al. (1999) Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res 59:1820-4

Showing the most recent 10 out of 20 publications