proposal abstract). Despite the advent of new multimodal approaches for the treatment of oral cancer, the five year survival rates have not increased significantly in the past thirty years. To overcome the overall failure rate associated with the classical therapies, new concepts of patient management are currently being developed, including interventional prevention strategies, bioimmunotherapy, and gene therapy directed against specific targets involved in oral cancer. The development of these strategies dependent on the identification and characterization of aspects of the tumorigenesis process that permit the growth and survival of the tumors. Critical in the development of new therapeutic strategies therefore is the development of an understanding of the biological mechanisms underlying the tumorigenic process, including the characterization of the sequential genetic and phenotypic changes which accompany oral tumorigenesis. This knowledge should help to identify aspects of the tumorigenic pathway that might serve as targets for future therapeutic interventional strategies. Cytogenetic and molecular analyses of oral cavity tumors and oral cavity premalignant lesions have recently uncovered a number of recurrent genetic alterations which are thought to accumulate during multistep tumorigenesis and lead to interactions that create the tumor phenotype. While the function of many of these genes have been identified in the in vitro and transgenic animal model systems, the functional consequences of these genetic changes for the in vivo tumorigenesis process in oral cavity tissue is poorly understood. One common specific genetic event in oral cancer development is amplification of a gene region on chromosome 11q13. This chromosome region includes a number of genes of potential functional importance for oral cancer development, including the cyclin D1 gene, which has been shown to be an important driving force in cell cycle progression. Preliminary studies have shown that cyclin D1 amplification frequently occurs early in the tumorigenesis process (i.e., hyperplasia to dysplasia) and dysregulation of cyclin D1 expression appears to precede cyclin D1 amplification in these tumors. Moreover, these studies suggest that cyclin D1 functionally cooperates with another gene defect common in oral tumors, p16/INK4 alterations, in enhancing genomic instability, a major driving force in oral tumorigenesis. To better understand the in vivo consequences of specific genetic changes during human oral multistep tumorigenesis, the principal investigator proposes to carry out in situ cell and molecular biology studies on oral cavity tumor specimens that demonstrate a continuous histologic evolution from normal adjacent epithelium through premalignant histology to invasive tumor. In particular, the principal investigator proposes the following specific aims: 1) determine the frequency that chromosome 11q13 gene amplification precedes tumor development during oral tumorigenesis 2) determine the functional consequence of chromosome 11q13 amplification for the multistep process 3) determine the mechanism involved in chromosome 11q13 gene amplification in vivo 4) determine if other amplification of genes in other chromosomal regions occur early along a similar pathway. The elucidation of the pathways and forces that drive the multistep tumorigenesis process in the oral cavity should provide new targets for chemopreventive intervention and therapeutic management that will lead to decreased morbidity resulting from oral cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013157-02
Application #
6175897
Study Section
Special Emphasis Panel (ZDE1-GH (03))
Program Officer
Sandberg, Ann
Project Start
1999-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$208,211
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
Hittelman, Walter N; Liao, Yong; Wang, Li et al. (2010) Are cancer stem cells radioresistant? Future Oncol 6:1563-76
Milas, Luka; Hittelman, Walter N (2009) Cancer stem cells and tumor response to therapy: current problems and future prospects. Semin Radiat Oncol 19:96-105
Izzo, Julie G; Luthra, Rajyalakshmi; Wu, Tseung-Teh et al. (2007) Molecular mechanisms in Barrett's metaplasia and its progression. Semin Oncol 34:S2-6
Izzo, Julie G; Wu, Tsung-Teh; Wu, Xifeng et al. (2007) Cyclin D1 guanine/adenine 870 polymorphism with altered protein expression is associated with genomic instability and aggressive clinical biology of esophageal adenocarcinoma. J Clin Oncol 25:698-707
Izzo, Julie G; Malhotra, Usha; Wu, Tseung T et al. (2005) Impact of cyclin D1 A870G polymorphism in esophageal adenocarcinoma tumorigenesis. Semin Oncol 32:S11-5
Izzo, Julie G; Papadimitrakopoulou, Vassiliki A; Liu, Diane D et al. (2003) Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 95:198-205
Richie, Christopher T; Peterson, Carolyn; Lu, Tao et al. (2002) hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage. Mol Cell Biol 22:8635-47
Papadimitrakopoulou, V A; Izzo, J; Mao, L et al. (2001) Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development. Clin Cancer Res 7:3127-34
Hittelman, W N (2001) Genetic instability in epithelial tissues at risk for cancer. Ann N Y Acad Sci 952:1-12