In chemoprevention of head and neck squamous carcinoma (HNSCC), new approaches must consider the sustained epigenetic effects of tobacco use on host molecular mechanisms and identification of novel agents with limited toxicity and acceptable therapeutic ratio. Smoking and nutrition have been identified as significant factors that contribute to carcinogenesis and prognosis of these cancers. Epigenetic CpG island methylation in the tumor promoter gene p16 is frequent in HNSCC and in the mucosa of smokers, premalignant dysplastic tissue and in non-cancerous tissue adjacent to proven malignancies suggesting an important role in early carcinogenesis and second primary malignancy. An important downstream target of p16 that may play a central role in HNSCC carcinogenesis is COX-2. COX-2 over expression is common in premalignant and malignant mucosa and is associated with smoking and chronic inflammation. When blocked, COX-2 decreases tumor growth and invasiveness. COX-2 is influenced by EGFR signaling and p16 inactivation which are commonly perturbed in HNSCC. We propose to identify frequency of gene methylation for p16 and 3 other candidate genes, gene expression alterations and related serum biomarkers associated with clinical outcome using our extensive retrospective tissue and clinical data resource. We will prospectively validate and expand these data and determine specific effects of a tailored smoking cessation program on modulation of identified biomarkers. A Phase II trial is proposed to determine if preoperative soy isoflavones can modulate these markers. Soy isoflavones have been shown to reverse p16 methylation, decrease COX-2 expression and modulate VEGF, IL6, tumor proliferation, angiogenesis and apoptosis. We hypothesize that suppressor gene hypermethvlation in tumor and adjacent non-tumor mucosa and associated molecular changes in downstream targets such as COX-2. VEGF. EGFR and IL6 are associated with clinical outcome and can be abrogated by soy isoflavone supplementation and smoking cessation. We will use pyrosequencing to measure methylation of p16 and three other candidate genes in pretreatment samples from both retrospective and prospective patients and correlate with outcome. We will determine expression of EGFR, COX-2, VEGF, p53 , p65,a6p4 integrin, HPV-16, Bcl-xL in tissue and levels of VEGF, IL6, HGF and 15-Ft2-isoprostane in serial serum and saliva samples from our prospective patients. This comprehensive proposal will investigate the molecular rationale for future soy isoflavone and smoking cessation prevention trials and identify intermediate molecular endpoints. These data will help define high risk patients according to biomarkers and smoking status who might benefit most from chemoprevention. Studies of upregulated gene profiles associated with tumor suppressor gene hypermethylation may identify new target genes for future study.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097248-10
Application #
8382512
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$414,405
Indirect Cost
$87,645
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Matsumoto, Camila S; Almeida, Luciana O; Guimarães, Douglas M et al. (2016) PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells. Oncotarget 7:42393-42407
Pearson, Alexander T; Finkel, Kelsey A; Warner, Kristy A et al. (2016) Patient-derived xenograft (PDX) tumors increase growth rate with time. Oncotarget 7:7993-8005
Arthur, Anna E; Bellile, Emily L; Rozek, Laura S et al. (2016) Pretreatment serum xanthophyll concentrations as predictors of head and neck cancer recurrence and survival. Head Neck 38 Suppl 1:E1591-7
Walline, Heather M; Komarck, Christine M; McHugh, Jonathan B et al. (2016) Genomic Integration of High-Risk HPV Alters Gene Expression in Oropharyngeal Squamous Cell Carcinoma. Mol Cancer Res 14:941-952
Walline, Heather M; Carey, Thomas E; Goudsmit, Christine M et al. (2016) High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV. Mol Cancer Res :
Choi, Seung Hee; Terrell, Jeffrey E; Bradford, Carol R et al. (2016) Does Quitting Smoking Make a Difference Among Newly Diagnosed Head and Neck Cancer Patients? Nicotine Tob Res :
Zhang, Yanxiao; Koneva, Lada A; Virani, Shama et al. (2016) Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures. Clin Cancer Res 22:4735-45
Rudy, Shannon F; Brenner, J Chad; Harris, Jennifer L et al. (2016) In vivo Wnt pathway inhibition of human squamous cell carcinoma growth and metastasis in the chick chorioallantoic model. J Otolaryngol Head Neck Surg 45:26
Swiecicki, Paul L; Bellile, Emily; Sacco, Assuntina G et al. (2016) A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drugs 34:481-9
Prince, Victoria; Bellile, Emily L; Sun, Yilun et al. (2016) Individualized risk prediction of outcomes for oral cavity cancer patients. Oral Oncol 63:66-73

Showing the most recent 10 out of 233 publications