Oral cancer is the seventh most common form o_ cancer and causes 8,000 deaths in the United States each year and 128,000 worldwide. Similar to other tumor types, it is widely accepted that the formation of oral cancer is a multi-step process that results from the accumulation of genetic alterations. The high frequency of genetic and epigenetic alterations found in certain genes strongly suggests a causal role in thq development of oral cancer. Our long-term objective is to generate transgenic mice carrying inducibh genetic alterations that closely mimic some of the most common mutations found in human cancer of the or_ cavity. Although a large number of genetic alterations have been reported in oral cancer patients, three different molecular pathways seem to be the major targets of mutations, namely the p53, retinoblastoma (Rb) and Epidermal Growth Factor Receptor (EGFR) signaling pathways. Accordingly, the gene alterations most frequently found in oral cancer include EGFR overexpression, p53 mutations (such as the gain-of- function p53R175H) and inactivation of the INK4a/ARF locus, which functions at least in part as a negative regulator of the Rb pathway. We hypothesize that these mutations that have a high incidence in oral cancer patients play a causal role in the development of cancer of the oral cavity. To test this hypothesis we will use an inducible system to generate mouse models that exhibit p53 mutations, EGFR overexpression or inactivation of the INK4a/ARF locus only in the oral cavity. These models have several advantages over conventional transgenic/knockout models: the mutation can be targeted to a restricted area of the tissue and the moment of tumor initiation can be chosen. Therefore, they will closely mimic the sporadic focal accumulation of somatic mutations found in human tumors. These mouse models will be useful not only to better understand the molecular mechanisms of oral cancer development, but also as preclinical models for testing therapeutic agents for prevention and intervention of oral cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015344-05
Application #
7335597
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Shirazi, Yasaman
Project Start
2005-01-13
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
5
Fiscal Year
2008
Total Cost
$350,204
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030