We and others have demonstrated that silencing of tumor suppressor genes associated with promoter hypermethylation is a common feature of many human cancers. We have identified several novel tumor suppressor genes inactivated by promoter hypermethylation, as well as candidate genes for use in detection strategies. We propose continue to identify and characterize hypermethylated genes in squamous cell carcinoma of the head neck (HNSCC) and will identify novel promoter hypermethylated genes by: (1) A candidate gene approach based on testing genes found to be hypermethylated in other tumors or on the functional structure and biologic plausibility of the candidate gene and (2) A functional screen looking for genes that are up-regulated following treatment with demethylating agents (5-Aza-deoxycytidine). Newly identified hypermethylated genes will be characterized for functional significance and biologic activity in tumor progression. We will apply a modified pharmacologic unmasking approach to define promoter hypermethylated genes whose inactivation contributes to drug resistance to conventional chemotherapeutic and pathway (EFGR) directed therapy. Candidate hypermethylated tumor suppressor genes will be validated in drug resistant cell lines by transfection of candidate genes in in vitro and in vivo mouse models. These genes will then be validated in prospective trials and retrospective cohorts treated with conventional chemotherapy and EGFR pathway specific agents. Novel promoter hypermethylatedtargets will be incorporated into a second SPORE proposal (project #2) for use as markers for the early detection and monitoring of patients with head and neck cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
5P50DE019032-10
Application #
8308987
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
2012-08-12
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
10
Fiscal Year
2011
Total Cost
$313,415
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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