Soft tissue sarcoma is a devastating malignancy involving tumors of putative mesenchymal cell origin. The soft tissue sarcoma five year overall survival rate of 50 percent has been stagnant for the past thirty years. No fundamentally new therapies have been introduced since the inception of doxorubicin multi-drug chemotherapy regimens in the early 1970s. The most frequently encountered genetic mutation in soft tissue sarcoma is alteration in the p53 tumor suppressor gene, which occurs in 30-60 percent of all such tumors. Brisk neovascularization at the sarcoma:normal tissue interface is macroscopically observable and occasionally can even compromise surgical resectability. Large central cores of hypoxic tumor necrosis are seen as these malignancies proliferate and outstrip their blood supply. An emerging awareness about tumor angiogenesis has prompted much interest in exploiting this component of the malignant phenotype as a potential therapeutic target. While little is known about angiogenesis in soft tissue sarcoma, the interrelationship between p53 mutation, tumor hypoxia leading to nitric oxide induction, and vascular endothelial growth factor (VEGF) has prompted the applicant to consider the following specific aims: 1) Investigate the pathobiologic impact of p53 gene mutation on VEGF induction in STS. 2) Examine the molecular mechanisms underlying p53 gene regulation of VEGF in STS. 3) Develop experimental molecular therapeutic approaches that inhibit STS progression by targeting mutated p53 gene and VEGF expression. To address these specific aims, an experimental design will be utilized that incorporates an in depth molecular based examination of the biology and mechanisms underlying p53 induction of VEGF, as well as the role of nitric oxide in this process. Preclinical therapeutic interventions will also be considered utilizing wild-type p53 gene restoration therapy combined with anti-VEGF approaches (antisense VEGF and anti-VEGF receptor monoclonal antibody treatments). Isolated limb perfusion is already accepted as a standard means of delivering high dose chemotherapy to extremity sarcoma. A nude rat human sarcoma xenograft model already established in the applicant's laboratory will be used as a novel means of delivering the above therapeutic constructs directly into human sarcoma xenografts. It is hoped that by successfully completing this project the applicant will enhance our knowledge of the regulatory interaction between p53 and VEGF in soft tissue sarcoma, leading to subsequent clinical trials in humans that will address these molecular derangements, perhaps via novel isolated limb perfusion gene delivery systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA067802-06
Application #
6376157
Study Section
Special Emphasis Panel (ZRG1-ET-2 (04))
Project Start
1995-09-30
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2001
Total Cost
$236,250
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Hannay, J; Davis, J J; Yu, D et al. (2007) Isolated limb perfusion: a novel delivery system for wild-type p53 and fiber-modified oncolytic adenoviruses to extremity sarcoma. Gene Ther 14:671-81
Das, Parimal; Kotilingam, Dhanasekaran; Korchin, Borys et al. (2007) High prevalence of p53 exon 4 mutations in soft tissue sarcoma. Cancer 109:2323-33
Hannay, Jonathan A F; Liu, Juehui; Zhu, Quan-Sheng et al. (2007) Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation. Mol Cancer Ther 6:1650-60
Zhang, Lianglin; Hannay, Jonathan A F; Liu, Juehui et al. (2006) Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance. Cancer Res 66:8770-8
Liu, Jue; Zhan, Maocheng; Hannay, Jonathan A F et al. (2006) Wild-type p53 inhibits nuclear factor-kappaB-induced matrix metalloproteinase-9 promoter activation: implications for soft tissue sarcoma growth and metastasis. Mol Cancer Res 4:803-10
Zhan, Maocheng; Yu, Dihua; Liu, Juehui et al. (2005) Transcriptional repression of protein kinase Calpha via Sp1 by wild type p53 is involved in inhibition of multidrug resistance 1 P-glycoprotein phosphorylation. J Biol Chem 280:4825-33
Zhang, Lianglin; Yu, Dihua; Hicklin, Daniel J et al. (2002) Combined anti-fetal liver kinase 1 monoclonal antibody and continuous low-dose doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis. Cancer Res 62:2034-42
Hu, Mei; Nicolson, Garth L; Trent 2nd, Jonathan C et al. (2002) Characterization of 11 human sarcoma cell strains: evaluation of cytogenetics, tumorigenicity, metastasis, and production of angiogenic factors. Cancer 95:1569-76
Zhan, M; Yu, D; Lang, A et al. (2001) Wild type p53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression. Cancer 92:1556-66
Zhang, L; Yu, D; Hu, M et al. (2000) Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 60:3655-61

Showing the most recent 10 out of 19 publications