Thyroid cancer is the most common endocrine malignancy with an annual incidence of 21,000 in the U.S. 5- 10% of patients have advanced thyroid cancer that is unresponsive to standard therapy, and 1,500 patients die each year from this disease. There are Currently no effective therapies for patients with advanced thyroid cancer. Retinoid therapy (derivatives of vitamin A) is effective in some patients with leukemia, head &neck cancer, lung cancer and breast cancer. This therapy has shown some promise for patients with advanced thyroid cancer, but only 20-40% of patients responsd to retinoid treatment. We hypothesized that patients with advanced thyroid cancer would respond to retinoid therapy based on retinoic acid receptor (RAR a, b, gamma) and retinoid X receptor (RXR a, b, gamma) expression. While testing this hypothesis, we identified a unique pattern of expression of two receptors (RARb and RXRgamma) in thyroid cancer cell lines and tumor tissue. The expression of these receptors is associated with growth inhibition by synthetic retinoids, and this heterodimer (RARb /RXRgamma) may be critical in mediating the retinoid response. We have also shown that expression of another nuclear hormone receptor (PPARgamma) is associated with growth inhibition by thiazolidinediones (TZD), and may form a unique heterodimer with RXRgamma to mediate this response. Based on these preliminary results, we hypothesize that two unique heterodimer pathways are necessary and sufficient for response to retinoid and TZD treatment: RARb/RXRgamma, which mediates growth suppression and differentiation, and PPARgamma/RXRgamma, which mediates growth suppression and apoptosis. The goals of this proposal are to define the roles of the RXRgamma, RARb and PPARgamma nuclear hormone receptors in mediating response to retinoid and TZD therapy for advanced thyroid cancer through in vitro cell line models and in vivo mouse thyroid carcinoma models. We will also explore the role of leukemia inhibitory factor (identified by microarray analysis) as a direct mechanism through which the effects of retinoids and TZD mediate growth arrest in advanced thyroid carcinoma. Successful completion of these aims will provide a fundamental understanding of how retinoids and TZD affect cancer cell growth and differentiation, as well as identify molecular tools to design clinical studies that will be the basis of individualized therapy for patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA100560-05S1
Application #
7908326
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Forry, Suzanne L
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$149,896
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Pozdeyev, Nikita; Berlinberg, Adam; Zhou, Qiong et al. (2015) Targeting the NF-?B Pathway as a Combination Therapy for Advanced Thyroid Cancer. PLoS One 10:e0134901
Bauerle, Kevin T; Schweppe, Rebecca E; Lund, Gregory et al. (2014) Nuclear factor ?B-dependent regulation of angiogenesis, and metastasis in an in vivo model of thyroid cancer is associated with secreted interleukin-8. J Clin Endocrinol Metab 99:E1436-44
Wood, William M; Sharma, Vibha; Bauerle, Kevin T et al. (2011) PPAR? Promotes Growth and Invasion of Thyroid Cancer Cells. PPAR Res 2011:171765
Bauerle, Kevin T; Schweppe, Rebecca E; Haugen, Bryan R (2010) Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion. Mol Cancer 9:117
Schweppe, Rebecca E; Kerege, Anna A; French, Jena D et al. (2009) Inhibition of Src with AZD0530 reveals the Src-Focal Adhesion kinase complex as a novel therapeutic target in papillary and anaplastic thyroid cancer. J Clin Endocrinol Metab 94:2199-203
Klopper, Joshua P; Sharma, Vibha; Berenz, Andrew et al. (2009) Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression. Mol Cancer 8:16
Schweppe, Rebecca E; Kerege, Anna A; Sharma, Vibha et al. (2009) Distinct genetic alterations in the mitogen-activated protein kinase pathway dictate sensitivity of thyroid cancer cells to mitogen-activated protein kinase kinase 1/2 inhibition. Thyroid 19:825-35
Haugen, Bryan R; Cooper, David S; Emerson, Charles H et al. (2008) Expanding indications for recombinant human TSH in thyroid cancer. Thyroid 18:687-94
Schweppe, Rebecca E; Klopper, Joshua P; Korch, Christopher et al. (2008) Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab 93:4331-41
Klopper, Joshua P; Berenz, Andrew; Hays, William R et al. (2008) In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clin Cancer Res 14:589-96

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