MON-414 - Thyroid Hormone Receptor Beta (Trβ)-Selective Agonism Suppresses Tumorigenic Properties in Poorly Differentiated Thyroid Cancer Cells.

Poorly differentiated thyroid carcinoma (PDTC) is an aggressive thyroid malignancy characterized by limited therapeutic options, diagnostic challenges, and poor clinical outcomes. Prior studies have revealed that the thyroid hormone receptor beta (TRβ) functions as a tumor suppressor in anaplastic thyroid cancer (ATC). PDTC similarly exhibits an aggressive phenotype characterized by increased cell growth, migration, stem cell-like properties and resistance to therapy. In addition, PDTC exhibits loss of expression of thyroid specific proteins, thyroid differentiation markers, such as the sodium–iodide symporter (NIS) and proteins critical for synthesis of thyroid hormones. Activation of TRβ with the selective agonist Sobetirome (GC-1) has been shown to restore TRβ tumor-suppressive signaling in anaplastic thyroid cancer (ATC), yet its potential impact and genomic mechanisms in PDTC remain largely unexplored.
To address this gap, we evaluated GC-1 activity in PDTC cells using thyrosphere assays, metabolic measurements and live-cell imaging. T243 and THJ529 cells were cultured under sphere forming conditions and treated with increasing doses of GC-1 or ethanol control for seven days. GC-1 dose-dependently reduced the stem-like cell population. Resazurin-based cell viability assays demonstrated no reduction in cell viability, indicating that stem cell depletion was not due to cytotoxicity but rather disruption of stemness-associated programs. Live-cell imaging demonstrated dose-dependent suppression of cell growth, consistent with reduced tumorigenic capacity. RT-qPCR and Western blot analyses confirmed low basal yet detectable TRβ mRNA and protein levels in PDTC cells, consistent with pharmacologic activation by GC-1.
Ongoing studies combine multi-omic profiling and clonal tracking to determine how GC-1 alters stemness-associated transcriptional programs, chromatin accessibility, and clonal dynamics in PDTC. By integrating sphere models and PDTC-derived organoids, these studies will define whether GC-1 limits tumorigenicity by constraining self-renewal or promoting differentiation. This approach will establish a mechanistic framework for targeting residual TRβ activity in aggressive thyroid cancers and for identifying potential diagnostic biomarkers.

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