Project 1: Low-penetrance genes in the predisposition to papillary thyroid carcinoma

Project Leaders: Albert de la Chapelle, MD, PhD; Rebecca Nagy M.S.,CGC

The goals of Project 1 are to advance the current knowledge of PTC predisposition by determining the biological functions of identified risk mutations and determine if they predict thyroid cancer risk as well as tumor behavior. Investigators in Project 1 have published that several SNPs are highly associated with PTC, including two GWAS analyses using large patient populations with apparently sporadic disease. Candidate genes have been identified. A concept emerging is that long intergenic noncoding RNA genes (lincRNAs) are major players in thyroid cancer susceptibility, but the mechanisms involved need to be established. The goal will be to firmly identify genes that associate with PTC, determine the functions of these genetic changes, and determine if the genetic abnormality performs as a robust predictor of cancer risk and tumor behavior in patients with PTC.

Project 2: Biomarker Discovery and Personalized Intervention of Radioiodine Induced Salivary Gland Damage in Thyroid Cancer Patients

Project Leaders: Sissy Jhiang, PhD; Ricardo Carrau, MD

The primary goal of Project 2 is to improve the quality of life of long-term thyroid cancer survivors by developing novel approaches to eliminate or reduce salivary gland damage from radioactive iodine therapy: Patients diagnosed with thyroid cancer often enjoy long-term survivorship. One of the common therapies employed is I-131. Unfortunately, I-131 treatment causes permanent salivary gland damage in as many as 30% of treated patients causing lifelong pain, dry mouth, taste disturbances, and dental damage. It is now recognized that the previous standard preventive measures may worsen this side effect. By case–control and prospective studies, Project 2 will determine the best strategies for predicting and preventing this complication, develop and test new biomarkers that predict a likelihood of salivary gland dysfunction, and develop new therapies to prevent this important survivorship issue.

Project 3: Developing Combination Therapies for Medullary Thyroid Cancer

Project Leaders: Matthew Ringel, MD; Manisha Shah, MD

The overall goal of Project 3 is to improve treatments for patients with progressive medullary thyroid cancer (MTC). MTC metastasizes earlier than other forms of differentiated thyroid cancer and accounts for a disproportionate amount of disease-related mortality. Treatment with multikinase inhibitors (MKI) induces stable disease or non-durable partial remissions in ~50% of patients. Recently, vandetanib and cabozantinib received FDA approval for treating patients with metastatic progressive MTC. However, patients require lifelong treatment and acquire resistance, creating the critical need for new second line therapies. The goal of Project 3 is to identify strategies to treat patients with resistant MTC. A focused Phase II clinical trial will be performed based on an observed synergy of targeting RET, RAF, and MEK. Additional studies will identify pathways of resistance using state-of-the-art genetic and proteomic approaches. A third approach will be to target cyclin-dependent kinases, which play a role in MTC development and progression in vivo.

Project 4: Development and Validation of Novel Circulating Medullary Thyroid Cancer Markers

Project Leaders: Gilbert Cote, PhD; Steven Sherman, MD

The goal of Project 4 is to develop new biomarkers to assess medullary thyroid cancer progression, drug resistance, and early recurrence. The early identification of distant metastases and understanding the biological properties of metastasizing cells remain a challenge in MTC. Project 4 seeks to test several approaches to enhance detection of MTC progression using cell free DNA assays and circulating tumor cell (CTC) detection. The proposal builds upon the discovery of a MTC cancer stem cell subpopulation and the identification of cell-specific transcripts (PROM1, NKX2.2. and SOX2), that are upregulated by vandetanib treatment.

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