Thyroid Cancer Research Lab

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 present 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 Objectives

Our lab focuses on translational research in thyroid cancer. The principal investigator of the lab is a thyroid surgeon interested in research in thyroid cancer that can help improve the care of all patients with thyroid cancer. We 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 Mass General, 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.

Our lab works diligently on validating a novel assay which identifies the BRAF mutation in circulating thyroid cancer cells. We eventually hope to come fore with an easy, less invasive biomarker that will refine the workup an treatment of our patients.

One of the recent investigations in our laboratory is on the role of this immune checkpoint in the development and aggressiveness of thyroid cancer. In the last decade immunotherapy has been regaining attention as a potential strategy to fight cancer cells. The genetic variability of cancer cells causes these cell to express different kind of molecules on their surface which can be recognize as antigen by the immune cells of an individual patient. This recognition as ‘non-self’ antigen has the potential of promoting anti tumor immune response. However, there are inhibitory pathways that regulate the function of T lymphocytes and render these responses unsuccessful. These molecular interaction normally designed to modulate immune response, called “immune checkpoints”, are being used by the tumor to evade the immune system. Our laboratory focuses on the immune checkpoint PD-1/ PD-L1 in thyroid cancer. By using our novel imunocompetent in-vivo model we are trying to better understand the potential benefit of treatments aiming at blocking tumor evasion mechanisms. We are studying the potential mechanisms by which tumor cells over-express PD-L1 and the ways to interfere with this process. Our aim is to establish a firm base of preclinical data to support clinical trials using immunotherapies to treat patients with aggressive thyroid cancer.

Principal Investigator

Sareh Parangi, MD

Members

• Visnawath Gunda, PhD, postdoctoral fellow
• Eran Brauner, MD
• Salma Amin, BA
• Juan Carlos Fernandez-Del Castillo

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

Research Projects

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.
7. Exploring the importance of the immune checkpoint PD-1and PD-L1 in various types of thyroid cancer. Identifying the effect of PD-1/PD-L1 blockade in a pre clinical models and the effect of this therapy combined with already established drugs. Developing strategies to enhance the anti tumor immune response.
8. Discovering ways to overcome resistance of tumor cells to BRAFV600E targeted therapy.

The Thyroid Cancer Research Laboratory seeks interested individuals for one-two year research fellowships. Pre- or post-doctoral fellows or MDs from outside the United States should apply if they have funding provided by their governments or institutions by emailing their resume and two letters of recommendation to Sareh Parangi, MD

Help with obtaining Visas for accepted candidates may in some cases be processed through the Partners International Office. Surgical residents or medical students with funding from their own institutions or eligible for T32/T35 NIH funding should apply by sending their resume to Dr. Parangi.

Due to difficulty in teaching basic science techniques, periods of time less than one year cannot be spent in the lab with the exception of medical student summer projects. The lab is open to those interested in both basic/clinical and translational projects. Mass General encourages women and minority applicants to apply to this position.

View Dr. Parangi's recent publications at PubMed

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