Thyroid proliferative disorders, ranging from clinically silent nodular hyperplasia to adenomatous goiter, and including thyroid cancer, affect a large part of the United States population, with a higher prevalence in women than in men. Although most nodules are benign, approximately 5% of them develop malignant features, and it is hard to predict the fate of any specific lesion, using only morphological features. Our ability to predict or identify thyroid cancer among the highly prevalent condition of nodular thyroid disease would be greatly improved by the identification of pathways that correlate with increased nodule growth or ongoing thyroid dedifferentiation. Numerous clinical data have recently pointed to the PI3K/PTEN/AKT pathway as a crucial player in thyroid proliferative disorders. The broad, long-term objective of this project is to test the hypotheses that activation of the PI3K/AKT pathway induces a benign thyroid hyperproliferative disorder, that it crosstalks with estrogen signaling to determine a higher proliferation index and increased adenoma incidence in females, and that it facilitates malignant transformation upon development of cooperating genetic alterations. We propose to test these hypotheses through a direct in vivo approach in a genetically defined system, with the following specific aims:
Aim 1 : To characterize in vivo and ex vivo the functional and molecular alterations induced in the mouse thyroid by the activation of the PI3K/PTEN/AKT axis.
Aim 2 : To elucidate the mechanisms through which circulating estrogens increase thyrocyte proliferation and adenoma susceptibility in female mutant mice.
Aim 3 : To test in vivo and ex vivo the hypothesis that PI3K/AKT activation allows thyroid cells to overcome inhibitory feedback signals initiated by Ras activation, thus inducing malignant thyrocyte transformation.

Public Health Relevance

The ultimate challenge in """"""""thyroidology"""""""" is the prediction of thyroid cancer among the highly prevalent condition of nodular thyroid disease. Thus it would be ideal to define pathways that correlate with increased nodule growth or ongoing thyroid transformation. Our preliminary data demonstrate that chronic PI3K activity is sufficient, in vivo, to induce thyroid hyperplasia and to create fertile ground for neoplastic transformation. Consequently we are in a unique position to achieve in vivo a better understanding of the mechanisms responsible for the development of nodular thyroid disease and its progression to thyroid follicular neoplasms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128943-05
Application #
8403889
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Snyderwine, Elizabeth G
Project Start
2009-02-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$314,070
Indirect Cost
$124,871
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Orlacchio, Arturo; Ranieri, Michela; Brave, Martina et al. (2017) SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance. Cancer Res 77:6914-6926
Di Cristofano, Antonio (2017) SGK1: The Dark Side of PI3K Signaling. Curr Top Dev Biol 123:49-71
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Champa, Devora; Di Cristofano, Antonio (2015) Modeling anaplastic thyroid carcinoma in the mouse. Horm Cancer 6:37-44
Champa, Devora; Russo, Marika A; Liao, Xiao-Hui et al. (2014) Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression. Endocr Relat Cancer 21:755-67
Russo, Marika A; Kang, Kristy S; Di Cristofano, Antonio (2013) The PLK1 inhibitor GSK461364A is effective in poorly differentiated and anaplastic thyroid carcinoma cells, independent of the nature of their driver mutations. Thyroid 23:1284-93
Di Cristofano, Antonio (2013) Obesity and thyroid cancer: is leptin the (only) link? Endocrinology 154:2567-9
Sponziello, Marialuisa; Lavarone, Elisa; Pegolo, Enrico et al. (2013) Molecular differences between human thyroid follicular adenoma and carcinoma revealed by analysis of a murine model of thyroid cancer. Endocrinology 154:3043-53

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