Thyroid cancer is the most common endocrine malignancy and ranks as the sixth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 52,000 new cases in 2019. A majority of patients have differentiated thyroid cancer and are managed successfully with a combination of surgery and radioiodine (RAI) therapy. However, tumors may present or recur as RAI-refractory or metastatic, in which case they have a poorer prognosis and death is common. Among these, anaplastic thyroid cancer (ATC), although relatively rare, represents a true clinical emergency: ATC is typically unresectable at presentation, highly resistant to therapy, RAI-resistant, and associated with a median survival of less than 9 months when patients are treated with multimodal therapy, and less than 3 months with palliative care. Cytotoxic chemotherapy and radiation are generally ineffective in prolonging survival of ATC patients. Thus, ATC remains one of the most lethal tumors and needs novel, effective, and especially rational therapeutic approaches. The major obstacle to this goal is the lack of a detailed understanding of the pathways altered both in the early stages (drivers) and during progression of ATC. As the patient population is small, our mechanistic knowledge is based on the retrospective analysis of patient material and on cell lines often of dubious origin. We now know that TP53 is lost or mutated in 70% of ATCs, and that in almost 40% the PI3K cascade is constitutively activated. Additional common drivers include BRAF (40%) and RAS (27%) activating mutations. Despite this knowledge, it is increasingly clear that we are still missing a comprehensive wiring chart depicting all the interactions between different, cooperating driver pathways. Such detailed map is of paramount importance to design effective multidrug combinations that consider less known signaling conduits, mechanisms of resistance, and feedback pathway activation. The current application has two broad, long-term objectives. The first goal is to utilize a combination of in vivo, ex vivo, and in vitro approaches to test the hypothesis that activation and/or overexpression of the SGK1 protein kinase are integral and essential components of the neoplastic transformation process initiated by constitutive activation of PI3K, RAS, and SRC in thyroid epithelial cells and that SGK1 targeting is essential for effective inhibition of tumor growth. The second objective is to use genetically engineered mouse models, as well as cell culture approaches, to test the hypothesis that mutations in mTORC1-activating pathways, including loss of NF2 and activation of PI3K signaling, cooperate with oncogenic RAS by contributing crucial signals needed for RAS-mediated transformation of thyroid epithelial cells. This genetic interaction opens a window of opportunity for targeted therapeutic approaches.

Public Health Relevance

Approximately 2,000 patients with thyroid cancer die each year in the U.S., and many more suffer from progressive, symptomatic disease. The limited number of advanced thyroid cancer patients has been a major obstacle to our understanding of the molecular mechanisms involved in disease progression, as well as to the development of effective therapies. Furthermore, even when the driving oncogenic insults are known and targeted inhibitors are available, cancers invariably develop resistance to them. In this application, we leverage the power of mouse genetics and in vivo disease modeling to characterize novel pathways that are critical for thyroid cancer development and to define novel paradigms for rationally designed combinatorial therapies. Successful completion of the proposed studies will help map novel signaling pathways and design effective therapies, providing benefit not only to advanced thyroid cancer patients, but also to those with other tumor types sharing the same genetic alterations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128943-14
Application #
10062869
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yassin, Rihab R
Project Start
2009-02-01
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
De Martino, Daniela; Yilmaz, Emrullah; Orlacchio, Arturo et al. (2018) PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. Cancer Lett 439:56-65
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
Champa, Devora; Orlacchio, Arturo; Patel, Bindi et al. (2016) Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. Oncotarget 7:34453-71
Mio, Catia; Lavarone, Elisa; Conzatti, Ketty et al. (2016) MCM5 as a target of BET inhibitors in thyroid cancer cells. Endocr Relat Cancer 23:335-47
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

Showing the most recent 10 out of 17 publications