Non-melanoma (basal cell and cutaneous squamous cell carcinomas) skin cancer and melanoma are common human malignancies whose growth is controlled at least in part by T-lymphocyte mediate immune responses. There is great interest in developing new modalities which will enhance and exploit this host defense mechanism for therapeutic benefit. We have observed that cutaneous squamous cell carcinomas and melanomas exhibit a profound reduction in tumor growth when treated with the bacterial super- antigen Staphylococcal enterotoxin B (SEB). The response is immunologic in nature and is highly specific for malignant tissue, both in vivo and in vitro. SEB may thus have great potential as a immunodermatologic therapy for skin cancer. In this proposal, we plan to investigate the hypothesis that the bacterial super-antigen SEB causes selective destruction of non- melanoma and melanoma skin cancers by serving as a ligand between the tumor cell and cytotoxic T-lymphocytes. We will more fully assess the immunodermatologic potential of SEB as a therapy for skin cancer by studying the range of cutaneous tumors responsive to SEB immunodermatologic therapy. We will also assess the efficacy of mutants SEB as therapeutic agents in skin cancer in order to identify those regions of the molecule most important at causing regression of skin cancers. Studies will be performed to evaluate whether inhibition of tumor cell growth by SEB and T-cells is cytotoxic in nature. Experiments will be conducted to identify the molecule on cutaneous squamous cell carcinomas to which SEB binds that allows it to inhibit the growth of cutaneous tumors. We will be particularly interested in determining whether SEB binding to major histocompatibility complex class I and class II molecules plays a role in the response. Because SEB limits the growth of malignant cells, but has little effect on keratinocytes from which these tumors are derived, we will investigate whether this is due to differential binding on SEB to tumor cells versus normal keratinocytes, differences in the expression of the adhesion molecule ICAM-1 on these two cell types, or to differences in the Fas pathway in normal versus malignant keratinocytes. Finally, experiments will be performed to precisely define the characteristics of the T-cell most effective at causing SEB-induced regression of cutaneous tumors. The ultimate goal of this proposal is to generate new knowledge that can be used to develop new and better strategies for the control of non-melanoma and melanoma skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079820-03
Application #
6342123
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hecht, Toby T
Project Start
1999-01-06
Project End
2003-12-31
Budget Start
2001-01-11
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$205,934
Indirect Cost
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Shi, Yang; Elmets, Craig A; Smith, Jeffery W et al. (2007) Quantitative proteomes and in vivo secretomes of progressive and regressive UV-induced fibrosarcoma tumor cells: mimicking tumor microenvironment using a dermis-based cell-trapped system linked to tissue chamber. Proteomics 7:4589-600
Huang, Chun-Ming; Ananthaswamy, Honnavara N; Barnes, Stephen et al. (2006) Mass spectrometric proteomics profiles of in vivo tumor secretomes: capillary ultrafiltration sampling of regressive tumor masses. Proteomics 6:6107-16
Huang, Chun-Ming; Wang, Chao-Cheng; Kawai, Mikako et al. (2006) Surfactant sodium lauryl sulfate enhances skin vaccination: molecular characterization via a novel technique using ultrafiltration capillaries and mass spectrometric proteomics. Mol Cell Proteomics 5:523-32
Huang, Chun-Ming; Wang, Chao-Cheng; Barnes, Stephen et al. (2006) In vivo detection of secreted proteins from wounded skin using capillary ultrafiltration probes and mass spectrometric proteomics. Proteomics 6:5805-14
Huang, Chun-Ming; Wang, Chao-Cheng; Kawai, Mikako et al. (2006) In vivo protein sampling using capillary ultrafiltration semi-permeable hollow fiber and protein identification via mass spectrometry-based proteomics. J Chromatogr A 1109:144-51
Mantena, Sudheer K; Meeran, Syed M; Elmets, Craig A et al. (2005) Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. J Nutr 135:2871-7
Roy, Anshu M; Baliga, Manjeshwar S; Elmets, Craig A et al. (2005) Grape seed proanthocyanidins induce apoptosis through p53, Bax, and caspase 3 pathways. Neoplasia 7:24-36
Huang, Chun-Ming; Shi, Zhongkai; DeSilva, Tivanka S et al. (2005) A differential proteome in tumors suppressed by an adenovirus-based skin patch vaccine encoding human carcinoembryonic antigen. Proteomics 5:1013-23
Huang, Chun-Ming; Elmets, Craig A; van Kampen, Kent R et al. (2005) Prospective highlights of functional skin proteomics. Mass Spectrom Rev 24:647-60
Huang, Chun-Ming; Elmets, Craig A; Tang, De-chu C et al. (2004) Proteomics reveals that proteins expressed during the early stage of Bacillus anthracis infection are potential targets for the development of vaccines and drugs. Genomics Proteomics Bioinformatics 2:143-51

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