One approach to cancer therapy has been the use of differentiation to arrest the growth of tumor cells. In order to apply differentiation therapy to cancer treatment, a mechanistic understanding of differentiation in tumor cells must be attained including which factors, genetic or otherwise, abrogate or enhance the effects of the differentiation agent. Vitamin A compounds (retinoids) are modulators of epithelial cell proliferation and differentiation. Retinoids have been used successfully to prevent epithelial tumors. The initiation of retinoid regulated differentiation requires changes in gene expression mediated by a cascade of transcriptionally regulated proteins. These factors may include the retinoic acid receptors and classical transcription factors such as homeobox genes. Our goal for this study is to understand the mechanism of retinoid responsiveness by studying retinoid modulated expression of genes in a human squamous cell carcinoma of the oral cavity for which we have isolated cDNA clones. We will investigate how transcription factors participate in their regulation and whether the activation of oncogene(s) plays a role in the progression of cells to a differentiation resistant state. We will analyze how oncogenes affect expression of differentiation regulated genes and whether alterations in transcription factors influence the oncogene effects on retinoid responsiveness of human epithelial cells from the oral cavity. We seek to identify critical genetic changes in human head and neck cancers and study how they affect growth, differentiation and differentiation regulated gene expression in human squamous cell carcinoma cell lines from the head and neck. These genetic elements include oncogenes, growth factors and growth factor receptors. We will try to identify changes in these genes such as overexpression and amplification in squamous cell carcinoma cell lines which may alter their response to retinoid-based differentiation therapy. Utilizing cDNA clones of retinoic acid responsive genes which we have isolated, we will study the mechanism of their modulation in epithelial cells and epithelial cancer cell lines of the head and neck to see if they are regulated similarly before and after tumorigenic transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA052051-05S1
Application #
5207637
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Hildebrandt, Michelle A T; Lippman, Scott M; Etzel, Carol J et al. (2012) Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin Cancer Res 18:3705-13
Lee, J Jack; Wu, Xifeng; Hildebrandt, Michelle A T et al. (2011) Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients. Cancer Prev Res (Phila) 4:185-93
Wang, Jianming; Lippman, Scott M; Lee, J Jack et al. (2010) Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma. Carcinogenesis 31:1755-61
Zhang, Xiaofan; Yang, Hushan; Lee, J Jack et al. (2010) MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer. Carcinogenesis 31:2118-23
Wu, Xifeng; Spitz, Margaret R; Lee, J Jack et al. (2009) Novel susceptibility loci for second primary tumors/recurrence in head and neck cancer patients: large-scale evaluation of genetic variants. Cancer Prev Res (Phila) 2:617-24
William Jr, William N; Lee, J Jack; Lippman, Scott M et al. (2009) High-dose fenretinide in oral leukoplakia. Cancer Prev Res (Phila) 2:22-6
Papadimitrakopoulou, Vassiliki A; Lee, J Jack; William Jr, William N et al. (2009) Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 27:599-604
Kawaguchi, Hidetoshi; El-Naggar, Adel K; Papadimitrakopoulou, Vali et al. (2008) Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol 26:354-60
Wu, Xifeng; Gu, Jian; Dong, Qiong et al. (2006) Joint effect of mutagen sensitivity and insulin-like growth factors in predicting the risk of developing secondary primary tumors and tumor recurrence in patients with head and neck cancer. Clin Cancer Res 12:7194-201
Lippman, Scott M; Lee, J Jack (2006) Reducing the ""risk"" of chemoprevention: defining and targeting high risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res 66:2893-903

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