Targeting Thyroid Stimulating Hormone Receptors in Radioiodine Resistant Dedifferentiated Thyroid Cancer

Abstract

The most common type of thyroid cancer, differentiated thyroid cancer (DTC), is diagnosed by radioactive iodine whole body scanning (WBS) and treated with radiotherapy using iodine-131 (131I). The success of this diagnosis/treatment approach relies on the relatively selective localisation of the sodium/iodide symporter (NIS) in cells of the thyroid gland. However, in some de-differentiated thyroid cancers, NIS expression is lost. This results in the inability of WBS to stage the disease and it also decreases the effectiveness of treatment with 131I. A number of reports have shown that de-differentiated thyroid carcinomas, however, continue to express thyroid stimulating hormone receptor (TSHR). TSHR is, therefore, a potential target for the diagnosis and treatment of radioiodine resistant de-differentiated thyroid carcinoma. In this study an anti-TSHR monoclonal antibody (mAb9) and human recombinant TSH (rhTSH) were radiolabelled and evaluated for their potential use in the diagnosis and treatment of radioiodine resistant thyroid cancer. A number of radiolabelling methods and quality control experiments were initially carried out to ensure high purity radiolabelled mAb9 and rhTSH were produced. In vitro studies were conducted to assess the binding affinity of 125I-mAb9, 111In-mAb9 and 125I-rhTSH to the TSHR in thyroid cancer cell lines, TPC-1, FTC-133, and FRTL5, and in a TSHR transfected cell line, GPI. SPECT/CT animal studies were performed in mice to investigate whether 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to TSHR in the thyroid of mice in vivo. 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to GPI cells but did not bind specifically to the TSHR in FTC-133, TPC-1 and FRTL5 cells as well as to the thyroid of normal mice in vivo. Radiolabelled mAb9 and radiolabelled rhTSH are therefore unlikely to be of use in the diagnosis and treatment of radioiodine resistant de-differentiated thyroid cancer.