Squamous cell carcinoma of the head and neck (SCCHN) is a frequently fatal disease with few available therapeutic modalities. Information concerning the growth factors involved in the development and maintenance of SCCHN may improve treatment options; such an understanding has resulted in new approaches to therapy in some cancers such as anti-EGF receptor antibodies to treat squamous cell carcinoma of the lung. The possibilities for this type of therapy for SCCHN is unknown since the role of growth factors has yet to be examined in a systematic fashion. The epithelial growth factor, transforming growth factor alpha (TGF- alpha), which shares the same cell surface receptor, the epidermal growth factor receptor (EGFR), with epidermal growth factor (EGF), is a likely candidate in this regard. In our initial studies we have detected elevated levels of EGFR and TGF-alpha mRNA in fresh tissue samples of tumor and histologically normal mucosa excised from patients with SCCHN compared with levels in normal mucosa resected from patients without cancer. The overall goals of this project are: (1) to determine the molecular mechanism of this apparent upregulation of EGFR and TGF-alpha mRNA using SCCHN cell lines (DNA versus RNA transcription versus RNA message stability), (2) to confirm elevation of TGF-alpha and EGFR at the protein level in fresh tissues and SCCHN cell lines, (3) to demonstrate the existence of an autocrine regulatory pathway involving EGFR and its ligand, TGF-alpha, in selected SCCHN cell lines using proliferation assays with human recombinant TGF-alpha and monoclonal antibodies to receptor and ligand, (4) to attempt to interrupt this pathway in SCCHN cell lines with differentiation agents such as retinoic acid (RA); if RA inhibits proliferation, we will examine if RA acts through down- regulation of EGFR or TGF-alpha mRNA synthesis using Northern blot analysis, (5) to examine the production of EGFR and TGF-alpha mRNA in premalignant lesions such as oral leukoplakia and erythroplasia, (6) to document the cellular population(s) responsible for this increased production of EGFR and TGF-alpha mRNA in fresh tissue specimens using in situ RNA hybridization techniques. The demonstration of an autocrine growth pathway involving EGFR and its ligand, TGF-alpha, in SCCHN would be a major advance in our understanding of the pathogenesis of this cancer and would provide opportunities for new preventative and therapeutic strategies based on modulation of this pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Physician Scientist Award (K11)
Project #
5K11CA001760-05
Application #
2442884
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Project Start
1993-07-01
Project End
1998-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Endo, S; Zeng, Q; Burke, N A et al. (2000) TGF-alpha antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo. Gene Ther 7:1906-14
Grandis, J R; Drenning, S D; Zeng, Q et al. (2000) Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A 97:4227-32
Rubin Grandis, J; Zeng, Q; Drenning, S D (2000) Epidermal growth factor receptor--mediated stat3 signaling blocks apoptosis in head and neck cancer. Laryngoscope 110:868-74
Rubin Grandis, J; Melhem, M F; Gooding, W E et al. (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824-32
He, Y; Zeng, Q; Drenning, S D et al. (1998) Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter. J Natl Cancer Inst 90:1080-7
Grandis, J R; Zeng, Q; Drenning, S D et al. (1998) Normalization of EGFR mRNA levels following restoration of wild-type p53 in a head and neck squamous cell carcinoma cell line. Int J Oncol 13:375-8
Grandis, J R; Chakraborty, A; Zeng, Q et al. (1998) Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells. J Cell Biochem 69:55-62
Grandis, J R; Drenning, S D; Chakraborty, A et al. (1998) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. J Clin Invest 102:1385-92
Drenning, S D; Marcovitch, A J; Johnson, D E et al. (1998) Bcl-2 but not Bax expression is associated with apoptosis in normal and transformed squamous epithelium. Clin Cancer Res 4:2913-21
Rubin Grandis, J; Tweardy, D J; Melhem, M F (1998) Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res 4:13-20

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