The incidence of thyroid cancer is rising at the second fastest rate of all malignancies in the United States and has an increasing tumor-specific mortality annually, making it an important public health problem. The reasons for this increasing incidence and rising death rate are uncertain. The goal of the P01 application is to address the key issues relating to thyroid cancer predisposition, tumorigenesis, and progression in order to enhance the potential for both early diagnosis and the effective treatment of progressive disease. Based on extensive preliminary data from our group, we propose to: (1) examine and identify predisposing genes for papillary thyroid cancer, (2) determine the critical changes responsible for the development of follicular thyroid cancer in an inherited form of the disease, Cowden syndrome, using a novel animal model, and translate this into a scheme to enhance preoperative diagnosis of this form of thyroid cancer, (3) evaluate and identify the key mechanisms of thyroid cancer induction and dedifferentiation induced by the RET/PTC 1 oncogene, one of the most common genetic abnormalities in papillary thyroid cancer, using a second novel animal model system, and (4) determine key pathways involved in tumor invasion and motility for both follicular and papillary thyroid cancers focusing on the models developed in this P01, and then test novel agents directed at blocking these pathway in vitro and in vivo. Over the past six years, the PI's of the individual projects, and the leaders of the cores have created an environment to successfully perform this integrated P01 that is unique for thyroid cancer. This includes a substantial database, integration with pathology, and a record of successful collaborative genetics, laboratory, drug development, and clinical research as evidenced by approximately thirty co-authored publications. Thus, this P01 represents an integrated Bedside-to-Bench-to-Bedside approach targeting the key clinical issues confronting the diagnosis and management of patients with thyroid cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (O1))
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Snyderwine, Elizabeth G
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Mahdi, Haider; Mester, Jessica L; Nizialek, Emily A et al. (2015) Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study. Cancer 121:688-96
Lakshmanan, Aparna; Doseff, Andrea I; Ringel, Matthew D et al. (2014) Apigenin in combination with Akt inhibition significantly enhances thyrotropin-stimulated radioiodide accumulation in thyroid cells. Thyroid 24:878-87
Wójcicka, Anna; Czetwerty?ska, Ma?gorzata; ?wierniak, Micha? et al. (2014) Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma. Genes Chromosomes Cancer 53:516-23
Pringle, Daphne R; Vasko, Vasily V; Yu, Lianbo et al. (2014) Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. J Clin Endocrinol Metab 99:E804-12
McCarty, Samantha K; Saji, Motoyasu; Zhang, Xiaoli et al. (2014) BRAF activates and physically interacts with PAK to regulate cell motility. Endocr Relat Cancer 21:865-77
Lakshmanan, Aparna; Scarberry, Daniel; Shen, Daniel H et al. (2014) Modulation of sodium iodide symporter in thyroid cancer. Horm Cancer 5:363-73
Wojcicka, A; de la Chapelle, A; Jazdzewski, K (2014) MicroRNA-related sequence variations in human cancers. Hum Genet 133:463-9
Stechschulte, Lance A; Wuescher, Leah; Marino, Joseph S et al. (2014) Glucocorticoid receptor ? stimulates Akt1 growth pathway by attenuation of PTEN. J Biol Chem 289:17885-94
Ngeow, Joanne; Stanuch, Kim; Mester, Jessica L et al. (2014) Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 32:1818-24
Medici, Marco; Porcu, Eleonora; Pistis, Giorgio et al. (2014) Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet 10:e1004123

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