Phone: (303) 724-3921
Dr. Haugen has been studying potential mechanisms involved in thyroid neoplasia and cancer, including the roles of retinoic acid receptors (RAR, RXR), peroxisome proliferator activated receptors (PPAR), tumor immunology, and kinase signaling as novel therapeutic targets in advanced thyroid cancer. He has also been involved in proteomic analyses of the thyroid gland and thyroid tumors. Clinically, Dr. Haugen is interested in thyroid and pituitary disorders, particularly novel diagnoses for thyroid neoplasms and therapies for thyroid cancer.
The Src and Focal Adhesion Kinase (FAK) complex represents a common point of convergence of many oncogenic tyrosine kinase signaling pathways that regulate key cellular processes including proliferation, survival, invasion, and migration. FAK and Src are both overexpressed and/or activated in many types of cancer. Given the important role of FAK and Src signaling in tumorigenesis, FAK and Src represent valuable therapeutic targets. Recently, Src inhibitors, including AZD0530 (Saracatinib) and BMS-354825 (Dasatinib) have entered human clinical trials. FAK and Src signaling and the efficacy of Src inhibitors has not been studied in thyroid cancer. We have recently established that FAK and Src are phosphorylated in the majority of thyroid cancer cell lines (Schweppe et al 2009 J Clin Endocrinol Metab). We have further shown that treatment of PTC and ATC cells with Saracatinib selectively inhibits the growth and invasion of cells expressing elevated levels of phospho-FAK. Finally, we show that phospho-FAK is present in a subset of PTC tumor samples. These studies provide the first evidence that FAK is activated in PTC and ATC, and that the FAK-Src complex represents a viable therapeutic target for a subset of patients with advanced thyroid cancer. The goals of our current studies are to characterize the mechanisms by which certain cell lines are sensitive to Src inhibition to help direct therapy and identify new therapeutic targets.
In an effort to identify novel therapeutic targets, we are currently studying the role of NF kappa B signaling in thyroid cancer. We utilize a combination of cell line-based in vitro assays, as well as, human specimens and mouse models of thyroid cancer to study the NF kappa B-regulated molecular processes that govern thyroid cancer tumor development and progression. Thus far, we have implicated NF kappa B in thyroid cancer cell growth, invasion, and resistance to apoptotic stimuli. Our recent data suggests a more global role for NF kappa B in driving thyroid tumor angiogenesis. Our current research is focused on the transcriptional regulation of secreted cytokines/chemokines, such as interleukin-8, by NF kappa B.
The incidence of thyroid cancer, the most common endocrine malignancy, has more than doubled in the last 30 years. Despite the overall success of current therapies, 10-30% of patients develop recurrence and/or metastases. Novel adjuvant therapies could reduce recurrence rates and the need for additional surgery. Immune-based therapies are under investigation to treat many types of cancer. The success of these therapies requires a detailed understanding of the interaction between the tumor and the immune system. Our studies revealed that the presence of tumor-associated lymphocytes correlates with more aggressive disease in patients with papillary thyroid cancer (PTC). Upon further analysis, we identified regulatory T lymphocytes (Tregs) as a consistent component of the lymphocytic infiltrate and their relative frequency correlated with tumor size and extent of lymph node metastasis. Thus, as in many other types of cancer, the tumor environment is highly immune suppressive and the unproductive immune response may even encourage disease progression. These retrospective studies have lead to a prospective analysis of CD4+ T lymphocyte polarization using post-surgical fine needle aspirate biopsies of thyroid nodules and lymph nodes. This work may confirm the predictive value of Treg frequency in patients with PTC and will further define the T cell response to PTC. Future studies using in vitro co-culture systems and animal models will uncover mechanisms of immune suppression and allow us to test the potential of immune-base therapies for patients with recurrent disease.
Drs. Haugen and Schweppe recently received an NIH Challenge Grant (15-CA-103) along with Drs. James Fagin and Jeffrey Knauf at Memorial Sloan Kettering to generate a panel of comprehensively characterized thyroid cancer cell lines. We will apply global molecular and genomic approaches with novel computational analyses to the new and existing thyroid cancer cell lines to uncover pathways important in thyroid cancer development and progression.
1. Klopper JP, Sharma V, Bissonnette R, Haugen BR. Combination PPARgamma and RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2. PPAR Res. 2010;2010:729876. PUBMED
2. Schweppe RE, Kerege AA, Sharma V, Poczobutt JM, Gutierrez-Hartmann A, Grzywa RL, Haugen BR. 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. 2009 Aug;19(8):825-35. PUBMED
3. Schweppe RE, Kerege AA, French JD, Sharma V, Grzywa RL, Haugen BR. 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. 2009 Jun;94(6):2199-203. PUBMED
4. Klopper JP, Sharma V, Berenz A, Hays WR, Loi M, Pugazhenthi U, Said S, Haugen BR. Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression. Mol Cancer. 2009 Mar 6;8:16. PUBMED
5. Klopper JP, Berenz A, Hays WR, Sharma V, Pugazhenthi U, Janssen J, Singh M, Bissonnette RP, Haugen BR. In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clin Cancer Res. 2008 Jan 15;14(2):589-96. Erratum in: Clin Cancer Res. 2009 Jan 1;15(1):416. PUBMED
6. Schweppe RE, Klopper JP, Korch C, Pugazhenthi U, Benezra M, Knauf JA, Fagin JA, Marlow L, Copland JA, Smallridge RC and Haugen BR . Deoxyribonucleic Acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endo Metab, 93:4331-41, 2008. PUBMED
7. Netea-Maier RT, Hunsucker SW, Hoevenaars B, Helmke SM, Slootweg P, Hermus A, Duncan MW, and Haugen BR . Quantitative and Qualitative Protein Expression Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma. Cancer Research 68:1572-80, 2008 PUBMED
8. Golden W, Weber KB, Hernandez TL, Woodmansee WW, Sherman SI, and Haugen BR . Single-dose rexinoid rapidly and specifically suppresses serum thyrotropin in normal subjects. J Clin Endo Metab, 92:124-30, 2007 PUBMED
9. Cooper DS, Doherty GM, Haugen BR , Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI and Tuttle RM. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 16:109-142, 2006. PUBMED
10. Sharma V, Hays WR, Wood WM, Pugazhenthi U, St. Germain DL, Bianco AC, Krezel W, Chambon P and Haugen BR . Effects of Retinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis. Endocrinology 147:1438-1551, 2006. PUBMED
11. Haugen BR , Larson LL, Pugazhenthi U, Hays WR, Klopper JP, Kramer CA , and Sharma V. Retinoic acid and retinoid X receptors are differentially expressed expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to natural and synthetic retinoids. J Clin Endo Metab 89:272-280, 2004. PUBMED
12. Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, and Haugen BR . Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse. J Clin Invest 106:73-79, 2000. PUBMED
13. Haugen BR , Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham K, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels M, Becker DV, Maxon HR, Cavalieri RR, Spencer CA, McEllin K, Weintraib BD, and Ridgway EC. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endo Metab . 84:3877-3885, 1999. PUBMED
14. Sherman SI, Gopal J, Haugen BR , Chiu AC, Whaley K, Nowlakha P, Truglia JP, Yocum R and Duvic M. Central hypothyroidism associated with retinoid X receptor-selective ligands. New Eng J Med . 340:1075-1079, 1999. PUBMED