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Targeting the Thyroid-Stimulating Ho...

Gimblet, Grayson Robert,

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

Record Type:	Electronic resources : Monograph/item
Title/Author:	Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer // Grayson Robert Gimblet.
Author:	Gimblet, Grayson Robert,
Description:	1 electronic resource (172 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Pharmaceutical sciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31932654
ISBN:	9798315793366

Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer /
Gimblet, Grayson Robert,

Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer /Grayson Robert Gimblet. - 1 electronic resource (172 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

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.

English

ISBN: 9798315793366Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Anaplastic thyroid carcinoma

Targeting the Thyroid-Stimulating Hormone Receptor (TSHR) in Thyroid Cancer /
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500 $a Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
500 $a Advisors: Lapi, Suzanne E. Committee members: Jaskula-Sztul, Renata; McConathy, Jonathan E.; Willey, Christopher D.; Larimer, Benjamin M.
502 $b Ph.D. $c The University of Alabama at Birmingham $d 2025.
520 $a 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.
546 $a English
590 $a School code: 0005
650 4 $a Pharmaceutical sciences. $3 3173021
650 4 $a Chemistry. $3 516420
650 4 $a Oncology. $3 751006
653 $a Anaplastic thyroid carcinoma
653 $a Oncocytic thyroid carcinoma
653 $a Radioactive iodine
653 $a Thyroid cancer
690 $a 0572
690 $a 0485
690 $a 0992
710 2 $a The University of Alabama at Birmingham. $b Pharmacology and Toxicology. $e degree granting institution. $3 3828589
720 1 $a Lapi, Suzanne E. $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-12B.
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791 $a Ph.D.
792 $a 2025
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31932654