Massachusetts General Hospital

Thyroid cancer is a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. While the majority of patients with well-differentiated thyroid cancer presents with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. There remains a lack of alternative treatment for patients with these poorly differentiated tumors and these patients have a poor response to conventional treatment. Key molecules involved in the initiation of this process may prove potent targets for treatments. Our objective is to study certain key genetic and epigenetic changes seen more frequently in those patients who do poorly, and find out how exactly these genetic changes lead to more aggressive cancer behavior in those patients. In essence, we hope to use our new knowledge to predict which patients with thyroid cancer may do poorly and treat those more aggressively with novel targeted therapies directed at the specific genetic mutations that seem to worsen their prognosis. Some patients with thyroid cancers have a single mutation in an important gene called BRAF. This gene is the most commonly mutated in papillary thyroid cancer and activation of ERK pathway by this common mutation leads to progression with more invasive local disease, lymph node involvement and distant metastases. Moreover, this single mutation is associated with both loss of radioiodine avidity and cancer recurrence. The mechanisms by which this mutation and others induce invasion and distant spread are not fully understood. One of the major goals of our laboratory is to characterize the molecular changes that occur as a result of the BRAF mutation using human thyroid cancer cells and relevant in vivo models. The information we learn from the mechanisms involved in the development of invasive thyroid cancers will lead directly to better treatment for all patients with thyroid cancer, especially those with aggressive kinds of thyroid cancer. Studying how this mutation leads to invasiveness in the thyroid tumors will help find novel therapeutic targets for advanced papillary thyroid cancer. By analyzing this invasive pathway our eventual purpose is to look for this BRAF mutation in all thyroid cancer patients treated at the MGH, help identify those with thyroid cancers that have a higher chance for aggressive clinical behavior, and treat those particular patients with special therapies targeting this mutations.

Principal Investigator

Sareh Parangi, MD

Members

Visnawath Gunda, PhD – Postdoctoral fellow
Sushruta Nagarkatti, MD – Research fellow
Carmelo Nucera, MD PhD – Instructor

Major projects are listed below and use not only basic molecular laboratory techniques but also a multitude of other resources, including the MGH Endocrine Tumor Tissue Repository and the MGH Endocrine Surgery Clinical Database under the auspices of the Codman Center for Clinical Effectiveness.

1. Characterize the role of BRAF^V600E mutation in human thyroid cancer cell proliferation, migration, invasion and metastasis. Identify specific effects of BRAF mutation on transcriptional regulation of extracellular matrix genes.
2. To develop models of thyroid cancer which accurately reflect disease progression in patients with advanced thyroid cancer.
3. The role of angiogenesis and lymphangiogenesis in benign and malignant thyroid conditions.
4. Discover and test novel therapeutic targets for advanced papillary thyroid cancer.
5. Assess whether known preoperative molecular markers are reliable predictors of lymph node involvement or recurrence in papillary thyroid cancer to help identify those with thyroid cancers that have a higher chance for aggressive clinical behavior. Identify thyroid cancer-specific molecular biomarkers, which in the future might allow personalized thyroid cancer surgery.
6. Determine the role of prophylactic removal of regional lymph nodes in papillary thyroid cancer patients using a multicenter, randomized study protocol.

Selected Original Publications

1. Parangi S., Dietrich W., Christofori G., Lander E.S., and Hanahan D.Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma Cancer Research, December 15 1995; 55: 6071-6076.
2. Parangi S., O'Reilly M.O., Christofori G., Holmgren L., Grosfeld J., Folkman J., and Hanahan D. Antiangiogenic therapy of transgenic mice impairs de novo tumor growth Proc. Natl. Acad. Sci March 1996; 93: 2002-2007.
3. Arbiser J., Moses M.A., Fernandez, C., Ghiso N., Cao, Y., Klauber N., Frank, D., Brownlee M., Flynn E., Parangi S., Byers R. and Folkman J. Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathway Proc. Natl.Acad.Sci February 1997; 94: 861-866.
4. Zeng H, Datta K, Neid M, Li J, Parangi S, and Mukhopadhyay D.; "Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line" Biochem Biophys Res Commun. 2003 Feb 28; 302(1):46-55
5. Mitchell J. and Parangi, S; "Angiogenesis in Benign and Malignant Thyroid Disease", Mitchell J. and Parangi, S; "Angiogenesis in Benign and Malignant Thyroid Disease", Thyroid, Volume 15 (6) 494-510, June 2005
6. Zhang XF, Galardi E Duquette M, Delic, M Lawler J, and Parangi, S: "Anti-angiogneic treatment with Thrombospondin-1 Three type I repeat recombinant proteins in an Orthotopic Human Pancreatic Cancer model" Clinical Cancer Research, Mar 15; 11(6):2337-44; 2005
7. Zhang XF, Galardi E Duquette M, Lawler J, and Parangi, S: "Antiangiogenic Treatment with Three Thrombospondin-1 Type 1 Repeats versus Gemcitabine in an Orthotopic Human Pancreatic Cancer Model" Clinical Cancer Research, 11(15) 5622-5630, August 2005
8. Mitchell J.C Grant F.D.; Evenson A.R.; Parker J. A., Hasselgren PO; and Parangi, S.: "Pre-Operative Evaluation of Thyroid Nodules with 18FDG-PET/CT". Surgery, 138(6), 1166-1176, December 2005
9. Zhang XF, Connolly C, Duquette M, Lawler J , and Parangi, S: "Continuous Administration of the Three Thrombospondin-1 Type 1 Repeats Recombinant Protein Improves the Potency of Therapy in an Orthotropic Human Pancreatic Cancer Model". Cancer Letters, 2006 June 4
10. Zhang, XF, Xu J, Lawler J, Terwilliger E and Parangi S: Adeno-Associated Virus-Mediated Antiangiogenic Gene Therapy with Thrombospondin-1 Type 1 Repeats and Endostatin.” Clinical Cancer Research 2007 Jul 1; 13(13):3968-76
11. Nucera C, Goldfarb M, Hodin R and Parangi S.: "Role of B-RafV600E in differentiated thyroid cancer and preclinical validation of compounds against B-Raf^V600E". BBA Reviews on Cancer, 2009 Apr; 1795(2):152-61.
12. Zhang X, Kazerounian S, Duquette M, Perruzzi C, Nagy JA, Dvorak HF, Parangi S, and Lawler J.:Thrombospondin-1 Modulates VEGF Activity at the Receptor Level, FASEB Journal, June 15 2009
13. Ren B, Song K, Parangi S, Jin T, Ye M, Humphreys R, Duquette M, Zhang X, Benhaga N, Lawler J, Khosravi-Far R: A double hit to kill tumor and endothelial cells by TRAIL and Antiangiogenic 3 TSR: Cancer Res. 2009 May 1;69(9):3856-65.
14. Mekel M, , Stephen A. E., Gaz R. D., Hodin R. A., and Parangi S: "Thyroid surgery in octogenarians is associated with higher complication rates." Surgery, Surgery. 2009 Jul 10.
15. Mekel M, Stephen AE, Gaz, RD, Randolph GW, Lubitz CC, Nehs MA, Parangi S, and Hodin RA. "Surgical drains can be safely avoided in modified radical neck dissections for thyroid cancer", American Journal of Surgery, 2010 199(4):485-90
16. Nucera C, Nehs MC, Mekel M, Zhang X, Hodin R, Lawler J, Nose V, and Parangi, S: A novel orthotopic mouse model of human anaplastic thyroid carcinoma. Thyroid. 2009 Oct;19(10):1077-84.
17. Lubitz CC, Faquin WC, Yang J, Hodin RA, Gaz RD, Parangi S, Randolph G and Stephen AE "Clinical and Cytological Features Predicitve of Malignancy in Follicular Neoplasms" Thyroid. 2010 Jan;20(1):25-31.
18. Nucera C, Porello, A, Antonello ZE, Mekel M Nehs MC, Giordano TJ, Gerald D, Bejamin LE, Priolog C, Puxeddu E, Finn S, Jarzab B, Hodin RA, Pontercorvi A, Nose V, Lawler J, and Parangi, S: B-Raf^V600E and Thrombospondin-1 Promote Thyroid Cancer Progression. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10649-54. Epub 2010 May 24.
19. Mekel M, Nucera C, Hodin RA, and Parangi S: Surgical Implications of BRAF ^V600E mutation in fine needle aspiration of thyroid nodules., Am J Surg. 2010 Jul;200(1):
20. Nehs MC, Nagarkatti, S, Nucera C, Hodin RA, and Parangi, S: "Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer." Surgery. 2010 Dec;148(6):1154-62; discussion 1162.
21. Lubitz CC, Hunter GJ, Hamberg, LM, Parangi S, Ruan D, Gwande, A, Gaz RD, Randolph GW, Moore FD, Hodin RA, and Stephen AE : Accuracy of 4D-CT in Poorly-Localized Patients with Primary Hyperparathyroidism, Surgery. 2010 Dec;148(6):1129-37; discussion 1137-8.
22. Yip L, Kebebew E, Milas M, Carty SE, Fahey TJ, Parangi S, Zeiger MA, and Nikiforov YE: Summary statement: Utility of molecular marker testing in thyroid cancer. Surgery Dec, 2010 148(6): 1313-5
23. Nucera C, Lawler J, and Parangi, S: BRAF^V600E and microenvironment in thyroid cancer: a functional link to drive cancer progression. Cancer research in press
24. Nucera C, Lawler J, Hodin RA, and Parangi, S The BRAF^V600E mutation: what is it really orchestrating in thyroid cancer Oncotarget, 2010 Dec;1(8):751-6.
25. Nucera C, Nehs MA, Nagarkatti SS, Sadow PM, Mekel M, Fischer AH, Lin PS, Bollag GE, Lawler J, Hodin RA, and Parangi S.: Targeting BRAFV600E with PLX4720 displays potent anti migratory and invasive activity in preclinical models of human thyroid cancer, The Oncologist in press