Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin-producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease after total thyroidectomy and central lymph node dissection. Moreover, there is no effective alternative to treat many of the debilitating symptoms associated with incurable MTC such as airway obstruction, flushing, abdominal pain and diarrhea. We have shown that activation of raf-1 through inhibition of GSK3B markedly suppresses cellular growth and reduces hormone secretion in human MTC cells in vitro and in vivo. In this proposal, we will explore the potential to utilize GSK3B inhibitors such as lithium to improve surgical outcomes for patient with metastatic MTC. In the first aim, we will develop 2 animal models of recurrent/persistent MTC to determine if GSK3B inhibitors will inhibit tumor growth and suppress hormone production in vivo. In the second aim, we plan to characterize a large number of human thyroid tumor samples, including MTC, and normal thyroid tissue for expression of raf-1 and GSK3B signaling pathway members. The data from these analyses will help predict which patients may be more likely to respond to lithium and other GSK inhibiting compounds. In the third aim, we will delineate the role of GSK3B in raf-1-mediated growth suppression and hormone inhibition. We have found that raf-1 activation also results in an increase in phosphorylated, inactive GSK3B, and that treatment of MTC cells with GSK3B inhibitors, such as lithium chloride and SB216763, can recapitulate the effects of raf-1. We will determine whether or not raf-1-mediated growth and hormone suppression is dependent upon GSK3B inhibition, and if GSK3B is the main downstream target of raf-1. In summary, the studies in this proposal represent a novel approach to understanding the biology of MTC, and may provide new insights to treating and palliating this disease.

Public Health Relevance

Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin- producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease after total thyroidectomy and central lymph node dissection. Moreover, there is no effective alternative to treat many of the debilitating symptoms associated with incurable MTC. We have shown that activation of raf-1 through inhibition of glycogen synthase kinase-3-beta (GSK3B) markedly suppresses cellular growth and reduces hormone secretion in human MTC cells in vitro and in vivo. In this proposal, we will explore the potential to utilize GSK3B inhibitors to improve surgical outcomes for patients with metastatic MTC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121115-05
Application #
8445159
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Timmer, William C
Project Start
2009-05-18
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$247,941
Indirect Cost
$77,662
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Jaskula-Sztul, Renata; Chen, Guojun; Dammalapati, Ajitha et al. (2017) AB3-Loaded and Tumor-Targeted Unimolecular Micelles for Medullary Thyroid Cancer Treatment. J Mater Chem B 5:151-159
Jaskula-Sztul, Renata; Xu, Wenjin; Chen, Guojun et al. (2016) Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy. Biomaterials 91:1-10
Chen, Guojun; Jaskula-Sztul, Renata; Harrison, April et al. (2016) KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy. Biomaterials 97:22-33
Yu, Xiao-Min; Jaskula-Sztul, Renata; Georgen, Maria R et al. (2016) Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression. Clin Cancer Res 22:3582-92
Jang, S; Yu, X-M; Odorico, S et al. (2015) Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation. Cancer Gene Ther 22:410-6
Jaskula-Sztul, Renata; Eide, Jacob; Tesfazghi, Sara et al. (2015) Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction. Mol Cancer Ther 14:499-512
Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93
Somnay, Y R; Dull, B Z; Eide, J et al. (2015) Chrysin suppresses achaete-scute complex-like 1 and alters the neuroendocrine phenotype of carcinoids. Cancer Gene Ther 22:496-505
Carter, Yvette M; Kunnimalaiyaan, Selvi; Chen, Herbert et al. (2014) Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth. Cancer Biol Ther 15:510-5
Carter, Yvette; Chen, Herbert; Sippel, Rebecca S (2014) An intact parathyroid hormone-based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy. J Surg Res 186:23-8

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