Boehm, Amanda L.
(2007)
INVESTIGATION OF THE MECHANISM AND THERAPEUTIC POTENTIAL OF A TRANSCRIPTION FACTOR DECOY TARGETING SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-3 (STAT3) FOR SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is the 5th most common cancer worldwide. Signal transducer and activator of transcription 3 (STAT3) is overexpressed in SCCHN and associated with decreased survival. A transcription factor decoy was designed to bind to the DNA binding domain of STAT3, abrogating expression of downstream target genes. The antitumor mechanisms of transcription factor decoys, including the STAT3 decoy, are incompletely understood. STAT3 forms heterodimers with STAT1 suggesting that the STAT3 decoy may interact with STAT1. We determined that the STAT1 pathway was functional in SCCHN cell lines. The STAT3 decoy inhibited STAT1-mediated expression of the target gene, IRF-1. Stimulation of the STAT1 pathway with IFN-ƒ× did not mitigate STAT3 decoy-mediated growth inhibition. STAT3 decoy-mediated inhibition of STAT1 signaling did not abrogate its antitumor effects in vitro. Studies using STAT3 knockout cells indicated that STAT3 is necessary for decoy-mediated growth inhibition. The STAT3 decoy was then studied in combination with an EGFR inhibitor and/or a Bcl-XL inhibitor as a therapeutic strategy for SCCHN. Targeting this pathway at several levels¡Xthe upstream receptor (EGFR), the intracellular transcription factor (STAT3), and the downstream target gene (Bcl-XL)¡Xhas not been previously investigated. Combined targeting of EGFR and STAT3 using erlotinib and the STAT3 decoy enhanced growth inhibition of SCCHN cells in vitro. The STAT3 decoy in combination with gossypol, a Bcl-XL inhibitor, resulted in enhanced growth inhibition. The triple combination of all 3 agents enhanced growth inhibition in vitro. These results indicate that targeting the EGFR-STAT3-Bcl-XL pathway at three distinct levels may be a promising treatment strategy for SCCHN.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
18 April 2007 |
| Date Type: |
Completion |
| Defense Date: |
2 April 2007 |
| Approval Date: |
18 April 2007 |
| Submission Date: |
3 April 2007 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Bcl-XL; cancer; EGFR; squamous cell carcinoma of the head and neck; STAT1; STAT3; transcription factor decoy |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04032007-154335/, etd-04032007-154335 |
| Date Deposited: |
10 Nov 2011 19:33 |
| Last Modified: |
19 Dec 2016 14:35 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6719 |
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