GSK3-beta Signaling in Medullary Thyroid Cancer

Summary

Principal Investigator: Herbert Chen
Affiliation: University of Wisconsin
Country: USA
Abstract: 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.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth
    Eric Weinlander
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    J Surg Res 190:191-7. 2014
  2. pmc Synergistic effect of pasireotide and teriflunomide in carcinoids in vitro
    Yash Somnay
    University of Wisconsin School of Medicine and Public Health, Endocrine Surgery Research Laboratories, Department of Surgery, Madison, USA
    Neuroendocrinology 97:183-92. 2013
  3. pmc Safety and feasibility of laparoscopic resection for large (≥ 6 CM) pheochromocytomas without suspected malignancy
    Yvette M Carter
    Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    Endocr Pract 18:720-6. 2012
  4. pmc Chrysin activates Notch1 signaling and suppresses tumor growth of anaplastic thyroid carcinoma in vitro and in vivo
    Xiao Min Yu
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Cancer 119:774-81. 2013
  5. pmc Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy
    Yuling Xiao
    Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin Madison, Madison, WI 53706, USA
    Nanoscale 4:7185-93. 2012
  6. pmc Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro
    Yash Somnay
    Endocrine Surgery Research Laboratories, Department of Surgery and University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA
    Anticancer Drugs 24:66-72. 2013
  7. pmc Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth
    Xiao Min Yu
    Department of Surgery, University of Wisconsin School of Medicine, Carbone Cancer Center, Madison, WI 53792 7375, USA
    Mol Cancer Ther 12:1276-87. 2013
  8. pmc Leflunomide suppresses growth in human medullary thyroid cancer cells
    Amal Alhefdhi
    Endocrine Surgery Research, Department of Surgery, University of Wisconsin, and Carbon Cancer Center, Madison, Wisconsin
    J Surg Res 185:212-6. 2013
  9. pmc MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition
    Jocelyn F Burke
    Department of Surgery, K3 705 Clinical Science Center, University of Wisconsin, Madison, WI, USA
    Ann Surg Oncol 20:3862-8. 2013
  10. pmc Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy
    Wenjin Xu
    Department of Biomedical Engineering, Wisconsin Institutes for Discovery, University of Wisconsin Madison, Madison, WI 53715, USA
    Nanoscale 5:9924-33. 2013

Scientific Experts

  • Herbert Chen
  • Megan Rist Haymart
  • Tabraiz A Mohammed
  • Joel T Adler
  • Muthusamy Kunnimalaiyaan
  • Renata Jaskula-Sztul
  • Li Ning
  • Mackenzie R Cook
  • Xiao Min Yu
  • Scott N Pinchot
  • Yash Somnay
  • April D Harrison
  • Yvette Carter
  • Jocelyn F Burke
  • Yvette M Carter
  • Darya Buehler
  • Celina Montemayor-Garcia
  • Rebecca S Sippel
  • Wenjin Xu
  • Tramanh Phan
  • Eric Weinlander
  • Selvi Kunnimalaiyaan
  • Amal Alhefdhi
  • Ricardo V Lloyd
  • Karine Pozo
  • Sara Tesfazghi
  • Sofia Asioli
  • Heather Hardin
  • Jacob Eide
  • Ajitha Dammalapati
  • Shaoqin Gong
  • Yuling Xiao
  • Madhuchhanda Roy
  • Barbara Zarebczan
  • Matthew Truong
  • Sam J Lubner
  • Mary Ndiaye
  • Vinita M Alexander
  • Jie Luo
  • Jui Yu Chen
  • Yi Qiang Cheng
  • Cheng Wang
  • T Clark Gamblin
  • Douglas Meyer
  • Logan Schlosser
  • Weihua Shan
  • Guiyang Hao
  • Roswitha Pfragner
  • Xiankai Sun
  • Kevin Simon
  • Fiemu E Nwariaku
  • Carolina Larrain
  • Gert Schwach
  • Patrick S Rush
  • Stanley Sidhu
  • Colin Korlesky
  • Anjali Gupta
  • Li Huei Tsai
  • Jonathan A Guevara
  • Veronika Siegl
  • Zhenying Guo
  • James A Bibb
  • James A Richardson
  • Justin Gundara
  • Aaron Redlich
  • Bruce G Robinson
  • Chunfeng Tan
  • Srikanth Pilla
  • Priyesh N Patel
  • Florian Plattner
  • Ailan Guo
  • Emely Castro-Rivera
  • Tim S Bugni
  • Edmond Richer
  • Pietro Antich
  • Kamal Ahmed
  • Gabriel Mettlach
  • Thomas P Wyche
  • Haggi Mazeh
  • Alireza Javadi
  • Michael Landowski
  • Noel R Peters
  • William R Schelman
  • Pongthep Pisarnturakit
  • Noelle K Loconte
  • Kyle D Holen
  • Daniel L Mulkerin
  • Kristen A Steffens
  • Lucy Wentworth
  • Sharon M Weber

Detail Information

Publications35

  1. pmc The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth
    Eric Weinlander
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    J Surg Res 190:191-7. 2014
    ..Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC...
  2. pmc Synergistic effect of pasireotide and teriflunomide in carcinoids in vitro
    Yash Somnay
    University of Wisconsin School of Medicine and Public Health, Endocrine Surgery Research Laboratories, Department of Surgery, Madison, USA
    Neuroendocrinology 97:183-92. 2013
    ..Here, we investigate the effects of SOM230 in combination with teriflunomide (TFN), a Raf-1 activator, in a human carcinoid cell line...
  3. pmc Safety and feasibility of laparoscopic resection for large (≥ 6 CM) pheochromocytomas without suspected malignancy
    Yvette M Carter
    Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    Endocr Pract 18:720-6. 2012
    ..To determine whether laparoscopic adrenalectomy in patients without radiologic evidence of cancer compromises the perioperative and long-term outcomes in patients with large (≥ 6 cm) pheochromocytomas...
  4. pmc Chrysin activates Notch1 signaling and suppresses tumor growth of anaplastic thyroid carcinoma in vitro and in vivo
    Xiao Min Yu
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Cancer 119:774-81. 2013
    ..It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC...
  5. pmc Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy
    Yuling Xiao
    Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin Madison, Madison, WI 53706, USA
    Nanoscale 4:7185-93. 2012
    ..Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers...
  6. pmc Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro
    Yash Somnay
    Endocrine Surgery Research Laboratories, Department of Surgery and University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA
    Anticancer Drugs 24:66-72. 2013
    ..In conclusion, MK-2206 suppresses carcinoid tumor growth, and alters its neuroendocrine phenotype, indicating that this drug may be beneficial for patients with carcinoid syndrome. These studies merit further clinical investigation...
  7. pmc Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth
    Xiao Min Yu
    Department of Surgery, University of Wisconsin School of Medicine, Carbone Cancer Center, Madison, WI 53792 7375, USA
    Mol Cancer Ther 12:1276-87. 2013
    ....
  8. pmc Leflunomide suppresses growth in human medullary thyroid cancer cells
    Amal Alhefdhi
    Endocrine Surgery Research, Department of Surgery, University of Wisconsin, and Carbon Cancer Center, Madison, Wisconsin
    J Surg Res 185:212-6. 2013
    ..In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells...
  9. pmc MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition
    Jocelyn F Burke
    Department of Surgery, K3 705 Clinical Science Center, University of Wisconsin, Madison, WI, USA
    Ann Surg Oncol 20:3862-8. 2013
    ..MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC...
  10. pmc Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy
    Wenjin Xu
    Department of Biomedical Engineering, Wisconsin Institutes for Discovery, University of Wisconsin Madison, Madison, WI 53715, USA
    Nanoscale 5:9924-33. 2013
    ..These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy. ..
  11. pmc The role of epithelial mesenchymal transition markers in thyroid carcinoma progression
    Celina Montemayor-Garcia
    Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, K4 436 Clinical Science Center, Box 8550, 600 Highland Avenue, Madison, WI, 53792, USA
    Endocr Pathol 24:206-12. 2013
    ....
  12. pmc The role of Cdk5 in neuroendocrine thyroid cancer
    Karine Pozo
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cancer Cell 24:499-511. 2013
    ..Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression. ..
  13. pmc An intact parathyroid hormone-based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy
    Yvette Carter
    Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin
    J Surg Res 186:23-8. 2014
    ..A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail?..
  14. pmc Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC-TT cell line
    Sara Tesfazghi
    University of Wisconsin Medical School, Madison, Wisconsin
    Cancer Med 2:734-43. 2013
    ..These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC. ..
  15. pmc Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth
    Yvette M Carter
    University of Wisconsin Endocrine Surgery Laboratory Madison, WI USA
    Cancer Biol Ther 15:510-5. 2014
    ..This study supports further investigation to elucidate the mechanism(s) by which GSK-3α inhibition downregulates the expression of NE tumor markers and growth of neuroblastoma. ..
  16. pmc Persistent hypertension after adrenalectomy for an aldosterone-producing adenoma: weight as a critical prognostic factor for aldosterone's lasting effect on the cardiac and vascular systems
    Yvette Carter
    Department of Surgery, Section of Endocrine Surgery, University of Wisconsin, Madison, Wisconsin, USA
    J Surg Res 177:241-7. 2012
    ..Here, we review the immediate and long-term medical outcomes of laparoscopic adrenalectomy in patients with an APA, and attempt to identify any distinctive sex differences in the management of resistant HTN...
  17. pmc Expression of epithelial-mesenchymal transition regulators SNAI2 and TWIST1 in thyroid carcinomas
    Darya Buehler
    Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, K4 436 Clinical Science Center, Madison, WI, USA
    Mod Pathol 26:54-61. 2013
    ..Our findings support the role of epithelial-mesenchymal transition in the development of anaplastic thyroid carcinoma...
  18. pmc A preclinical and clinical study of lithium in low-grade neuroendocrine tumors
    Sam J Lubner
    University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
    Oncologist 16:452-7. 2011
    ..Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs...
  19. pmc Down-regulation of Notch1 signaling inhibits tumor growth in human hepatocellular carcinoma
    Li Ning
    Am J Transl Res 1:358-66. 2009
    ..These results suggest for the first time that down-regulation of Notch1 signaling with curcumin is an attractive new therapeutic strategy for the treatment of patients with HCC...
  20. pmc Azacytidine induces cell cycle arrest and suppression of neuroendocrine markers in carcinoids
    Vinita M Alexander
    Endocrine Surgery Research Laboratory, Department of Surgery, University of Wisconsin Madison, Wisconsin, USA
    Int J Clin Exp Med 3:95-102. 2010
    ..The results suggest that DNMTIs may be a novel class of therapeutic agents that can effectively control tumor growth and the release of bioactive peptides in patients with NETs...
  21. pmc A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma
    Tabraiz A Mohammed
    D O, M S, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, Wisconsin 53792, USA
    Oncologist 16:835-43. 2011
    ..Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo...
  22. ncbi Papillary thyroid microcarcinomas: big decisions for a small tumor
    Megan Rist Haymart
    Division of Metabolism, Endocrinology, and Diabetes MEND, University of Michigan, Michigan, USA
    Ann Surg Oncol 16:3132-9. 2009
    ..The clinical significance of papillary thyroid microcarcinoma (PTMC) is debated, and therefore the rise in incidence of PTMC creates management dilemmas. The following study evaluates factors influencing decisions to treat...
  23. pmc Inhibition of the PI3K pathway suppresses hormonal secretion and limits growth in pheochromocytoma cells
    Joel T Adler
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, H4 722 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA
    World J Surg 33:2452-7. 2009
    ..We hypothesized that inhibition of the PI3K-Akt pathway would be a viable strategy to inhibit growth and hormonal secretion in pheochromocytoma cells...
  24. pmc MG-132 inhibits carcinoid growth and alters the neuroendocrine phenotype
    Jui Yu Chen
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    J Surg Res 158:15-9. 2010
    ..In this study, we investigate the ability of MG-132, a proteasome inhibitor, to inhibit carcinoid growth, the neuroendocrine phenotype, and its association with GSK-3beta...
  25. pmc Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid cell growth
    Mackenzie R Cook
    Endocrine Surgery Research Laboratory, University of Wisconsin, and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
    Mol Cancer Ther 9:429-37. 2010
    ..In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation...
  26. pmc Xanthohumol inhibits the neuroendocrine transcription factor achaete-scute complex-like 1, suppresses proliferation, and induces phosphorylated ERK1/2 in medullary thyroid cancer
    Mackenzie R Cook
    Endocrine Surgery Research Laboratory, Department of Surgery, University of Wisconsin, Madison, WI, USA
    Am J Surg 199:315-8; discussion 318. 2010
    ..Xanthohumol, a natural compound, has recently been shown to have anticancer properties. We thus hypothesized that xanthohumol would suppress growth by activating Raf-1 signaling, thus altering the malignant phenotype of MTC...
  27. pmc Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells
    Li Ning
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health and University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
    Mol Cancer Res 8:775-82. 2010
    ..Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells...
  28. pmc Resveratrol induces Notch2-mediated apoptosis and suppression of neuroendocrine markers in medullary thyroid cancer
    Matthew Truong
    Department of Surgery, University of Wisconsin, Madison, WI, USA
    Ann Surg Oncol 18:1506-11. 2011
    ..In this study, we hypothesized that the effects observed on carcinoid cells could be extended to MTC...
  29. pmc Hesperetin, a potential therapy for carcinoid cancer
    Barbara Zarebczan
    Department of Surgery, University of Wisconsin, Madison, WI, USA
    Am J Surg 201:329-32; discussion 333. 2011
    ..The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor...
  30. pmc Identification and validation of Notch pathway activating compounds through a novel high-throughput screening method
    Scott N Pinchot
    Endocrine Surgery Research Laboratory, Department of Surgery and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792, USA
    Cancer 117:1386-98. 2011
    ..Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells...
  31. pmc Expression of the active Notch1 decreases MTC tumor growth in vivo
    Renata Jaskula-Sztul
    Department of Surgery Endocrine Surgery Research Laboratories, UW Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin 53705, USA
    J Surg Res 171:23-7. 2011
    ....
  32. pmc Antiproliferative effect of chrysin on anaplastic thyroid cancer
    Tramanh Phan
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    J Surg Res 170:84-8. 2011
    ..However, the effect of this compound on ATC cells is not known. Thus, in this study, we evaluated the antiproliferative nature of chrysin in ATC cells...
  33. pmc Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride
    Joel T Adler
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    J Surg Res 159:640-4. 2010
    ..These compounds have been shown to limit growth and suppress hormonal secretion; thus, targeting different signaling pathways may be an effective treatment...