Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer

Grayson R Gimblet; Jason Whitt; Hailey A Houson; Diana Lin; Rachael Guenter; Tejeshwar C Rao; Dezhi Wang; John Ness; Manuel Lora Gonzalez; Madisen S Murphy; Andrea Gillis; Herbert Chen; John A Copland; Saad S Kenderian; Ricardo V Lloyd; Mariusz W Szkudlinski; Suzanne E Lapi; Renata Jaskula-Sztul

doi:10.1016/j.surg.2023.05.045

Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer

Surgery. 2024 Jan;175(1):199-206. doi: 10.1016/j.surg.2023.05.045. Epub 2023 Oct 31.

Authors

Grayson R Gimblet¹, Jason Whitt², Hailey A Houson³, Diana Lin⁴, Rachael Guenter⁵, Tejeshwar C Rao⁶, Dezhi Wang⁴, John Ness⁴, Manuel Lora Gonzalez⁴, Madisen S Murphy², Andrea Gillis², Herbert Chen⁷, John A Copland⁸, Saad S Kenderian⁹, Ricardo V Lloyd¹⁰, Mariusz W Szkudlinski¹¹, Suzanne E Lapi¹², Renata Jaskula-Sztul¹³

Affiliations

¹ Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL.
² Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
³ Department of Radiology, University of Alabama at Birmingham, Birmingham, AL.
⁴ Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
⁵ Department of Surgery, University of Alabama at Birmingham, Birmingham, AL. Electronic address: https://twitter.com/rachaelguenter.
⁶ Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL.
⁷ Department of Surgery, University of Alabama at Birmingham, Birmingham, AL. Electronic address: https://twitter.com/herbchen.
⁸ Department of Cancer Biology, Mayo Clinic Jacksonville, Jacksonville, FL.
⁹ Division of Hematology, Mayo Clinic Rochester, Rochester, MN.
¹⁰ Department of Pathology, University of Wisconsin-Madison, Madison, WI.
¹¹ Trophogen, Inc., Rockville, MD.
¹² Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. Electronic address: https://twitter.com/lapisuzanne.
¹³ Department of Surgery, University of Alabama at Birmingham, Birmingham, AL. Electronic address: rjsztul@uabmc.edu.

PMID: 37919223
DOI: 10.1016/j.surg.2023.05.045

Abstract

Background: Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium-iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer.

Methods: We immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with ⁸⁹Zr (t_1/2 = 78.4 h, β⁺ =22.7%) to produce [⁸⁹Zr]Zr-TR1402. We performed in vitro uptake assays in high-thyroid-stimulating hormone receptor and low-thyroid-stimulating hormone receptor-expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor-positive THJ529T tumors.

Results: Immunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [⁸⁹Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor-positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P < .01), with a similar difference seen in FTC133 cell lines (P < .0001). In vivo and biodistribution studies showed uptake of [⁸⁹Zr]Zr-TR1402 in thyroid-stimulating hormone receptor-expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection.

Conclusion: Our observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [⁸⁹Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor-positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer.

MeSH terms

Adenoma, Oxyphilic* / diagnostic imaging
Adenoma, Oxyphilic* / pathology
Animals
Cell Line, Tumor
Humans
Iodine Radioisotopes
Iodine*
Male
Mice
Mice, Nude
Positron-Emission Tomography / methods
Receptors, Thyrotropin* / metabolism
Thyroid Neoplasms* / diagnostic imaging
Thyroid Neoplasms* / pathology
Thyrotropin
Tissue Distribution

Substances

Iodine
Iodine Radioisotopes
Receptors, Thyrotropin
Thyrotropin

Supplementary concepts

Thyroid cancer, Hurthle cell

Grants and funding

R44 CA224376/CA/NCI NIH HHS/United States