Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer

Authors

Grayson Robert Gimblet, University of Alabama at Birmingham

Advisory Committee Chair

Suzanne Lapi

Advisory Committee Members

Benjamin Larimer

Christopher Willey

Jonathan Mcconathy

Renata Jaskula-Sztul

Document Type

Dissertation

Date of Award

1-1-2025

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Radioactive iodine (RAI) has been effective in the treatment of thyroid cancer, the most common endocrine neoplasia, since its introduction into clinical use over eighty years ago. However, not all patients benefit from RAI. Up to 20% of patients with well-differentiated thyroid cancer (WDTC) become radioactive iodine refractory (RAI-R). These RAI-R patients have 5-year survival rates of 50% and 10-year survival rates of 10%. In addition, more aggressive subtypes including oncocytic thyroid carcinoma (OC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) are less responsive to RAI therapy. Despite accounting for less than 5% of annual thyroid cancer cases, PDTC and ATC represent more than half of annual thyroid cancer mortality. To address the need for new diagnostic and therapeutic strategies in these patients, this study explores the thyroid-stimulating hormone receptor (TSHR) as an alternative target in thyroid cancer. We described the frequency of TSHR expression in OC (62%), PDTC (58%), and ATC (0%) relative to established expression patterns in WDTC (90%), with particular emphasis placed on expression patterns in RAI-R disease. As thyroid cancer loses endogenous TSHR expression in monolayer cell culture, we established cell lines with stable TSHR expression. We used these cell lines to evaluate TSHR-targeted radiopharmaceuticals. We designed PET radiopharmaceuticals based on two recombinant human thyroid-stimulating hormone analogues, TR1402 and thyrotropin-alfa, radiolabeled with 89Zr (t1/2 = 78.4 h, β+=23%). We performed in vitro assessments of these TSHR-targeted tracers including cell uptake, receptor blocking, internalization, and binding affinity. We evaluated tumor uptake and biodistribution with in vivo PET imaging and ex vivo biodistribution using a subcutaneous xenograft model established in male and female athymic nude mice. The results of these studies show targeting the TSHR is a promising approach for RAI-R and aggressive thyroid cancers. The PET tracers in this study can be used as the basis for future work to design a theranostic TSHR-targeted approach.

Comments

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Recommended Citation

Gimblet, Grayson Robert, "Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer" (2025). All ETDs from UAB. 6838.
https://digitalcommons.library.uab.edu/etd-collection/6838