Targeting the TSH receptor in thyroid cancer

Rowe, Christopher W; Paul, Jay P.; Gedye, Craig; Tolosa, Jorge; Bendinelli, Cino; McGrath, Shaun; Smith, Roger

doi:10.1530/erc-17-0010

Cited by 57 publications

(44 citation statements)

References 99 publications

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“…Although no significantly statistical differences in DCR, PFS, or OS were identified between the 131 I‐avid group and the non‐ 131 I‐avid group, superior ORR was achieved in the 131 I‐avid group. Nevertheless, inconsistency between ORR and survival and subtly inferior median PFS and OS were unexpectedly observed in the 131 I‐avid group, which may be partially explained by the higher ratios of patients with skeletal metastases (38.2% vs. 26.3% in PFS analyses and 40% vs. 26.7% in OS analyses, respectively), possibly higher tumor burden due to more courses of prior TSH stimulation before 131 I administration, and more attacks of probably overused 131 I . Therefore, early identification of patients with RR‐DTC with 131 I‐avid foci, timely halt of redundant 131 I therapy, and incorporating other therapeutic modalities may be of great value .…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study

Cheng

Jin

et al. 2020

The Oncologist

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Background. Because beneficial response and progression-free survival (PFS) were achieved by well-designed clinical trials with tyrosine kinase inhibitors (TKIs) in patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC), the overall survival (OS) and improvement of therapeutic outcomes in the real world have been anticipated. Subjects, Materials, and Methods. This prospective, singlecenter, real-world study assessed the predictive significance of clinicopathological features on disease control rate (DCR), objective response rate (ORR), PFS, and OS in a cohort of 72 patients with progressive RR-DTC treated with sorafenib at an initial dose of 200 mg twice daily. Results. Disease control, objective response, and biochemical effectiveness were achieved in 73.3%, 21.7%, and 77.9% of patients, respectively. The median PFS and OS were 17.6 and 28.9 months, respectively. Multivariate analyses showed that hand-foot syndrome (HFS) was an independent predictor for better DCR and ORR, and 131 I-avidity for higher ORR. In univariate analyses, longer PFS and OS were observed in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, pathologically well DTC, lung-only metastasis, absence of bone metastasis, biochemically nonineffective response, HFS, or radiological disease control. In multivariate analyses, only well DTC and ECOG PS ≤2 remained as independent prognostic factors for more favorable PFS and OS, respectively, whereas the absence of bone metastasis and biochemically nonineffective response independently predicted superior PFS and OS.Conclusion. This study demonstrated that clinicopathological features might play a vital role in predicting therapeutic outcomes in patients with progressive RR-DTC treated with sorafenib, warranting further optimization of candidates for TKIs. The Oncologist 2020;25:e668-e678 Implications for Practice: This prospective, single-center, real-world study was designed to investigate the significance of clinicopathological features in predicting response, progression-free survival, and overall survival in patients with progressive radioiodine-refractory differentiated thyroid cancer (DTC) treated with sorafenib. Multivariate analyses showed that hand-foot syndrome was an independent predictor for better response. Meanwhile, well DTC, Eastern Cooperative Oncology Group performance status ≤2, biochemically nonineffective response, and the absence of bone metastasis were independent prognostic factors for more favorable survival. This study demonstrated that clinicopathological features might play a vital role in predicting outcomes in sorafenib-treated patients with radioiodine-refractory DTC, warranting optimization of indications.

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Section: Discussionmentioning

confidence: 99%

Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study

Cheng

Jin

et al. 2020

The Oncologist

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“…The molecular function and clinical role of TSHR have been extensively explored in both benign and malignant thyroid tissues. Accordingly, it has been proposed that TSHR might serve as a candidate target for anticancer therapy [103]. Our current understandings of the anticancer role of TSHR in thyroid cancer come mostly from the effectiveness of the therapeutic strategies manipulating the TSH/TSHR signaling pathways, for example, by administration of levothyroxine.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, TSHR has a growth-promoting or oncogene-like function in thyroid cancer, although other co-existing mutations are required to establish a fully malignant phenotype. Nevertheless, clinically, the expression levels of TSHR seem to be downregulated in patients with more advanced stages of thyroid cancer, especially for those with poorly differentiated cell types, suggesting the existence of an uncharacterized selection/adaption mechanism [103].…”

Section: Tshr In Thyroid Cancer Cellsmentioning

confidence: 99%

The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells

Chu

Yeh

2020

Cells

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The thyroid stimulating hormone (TSH) and its cognate receptor (TSHR) are of crucial importance for thyrocytes to proliferate and exert their functions. Although TSHR is predominantly expressed in thyrocytes, several studies have revealed that functional TSHR can also be detected in many extra-thyroid tissues, such as primary ovarian and hepatic tissues as well as their corresponding malignancies. Recent advances in cancer biology further raise the possibility of utilizing TSH and/or TSHR as a therapeutic target or as an informative index to predict treatment responses in cancer patients. The TSH/TSHR cascade has been considered a pivotal modulator for carcinogenesis and/or tumor progression in these cancers. TSHR belongs to a sub-group of family A G-protein-coupled receptors (GPCRs), which activate a bundle of well-defined signaling transduction pathways to enhance cell renewal in response to external stimuli. In this review, recent findings regarding the molecular basis of TSH/TSHR functions in either thyroid or extra-thyroid tissues and the potential of directly targeting TSHR as an anticancer strategy are summarized and discussed.

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“…There are several practical in vivo applications of targeting the TSHR with K1-70 including controlling thyroid overactivity in Graves' disease and GO. In addition, blocking TSHR activity with K1-70 may benefit patients with thyroid cancer and Graves' disease [21][22][23]. Furthermore, the high binding affinity and specificity of K1-70 for the TSHR may be useful for imaging of tissues expressing the receptor and targeted drug delivery.…”

Section: In Vivo Practical Applications Of Tshr Researchmentioning

confidence: 99%

Practical applications of studies on the TSH receptor and TSH receptor autoantibodies

Furmaniak

Sanders

et al. 2020

Endocrine

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Studies on the TSH receptor (TSHR) have numerous practical applications in vitro and in vivo. For example human monoclonal autoantibodies (MAbs) to the TSHR are useful reagents for in vitro diagnostics. Measurement of TSHR autoantibodies (TRAbs) is helpful in diagnosis and management of autoimmune thyroid disease. Currently available highly sensitive and specific assays to measure TRAbs use the human TSHR MAb M22 instead of the TSH. Furthermore, preparations of the human TSHR MAb M22 are useful as the World Health Organisation International Standard for thyroid stimulating antibody and for calibration of the assays for measuring TRAbs. Preparations of thermostabilised TSHR extracellular domain have recently become available and this is likely to have an impact on improvements in specificity testing for TRAb assays. In addition the stable TSHR preparations have practical application for specific immunoadsorption of patient serum TRAbs. Human TSHR MAbs also have promising prospects as new therapeutics. Autoantibodies with TSHR antagonistic activities are "natural" inhibitors of TSHR stimulation and are expected to be helpful in controlling TSHR activity in patients with Graves' disease, Graves' ophthalmopathy and thyroid cancer.

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Targeting the TSH receptor in thyroid cancer

Cited by 57 publications

References 99 publications

Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study

Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study

The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells

Practical applications of studies on the TSH receptor and TSH receptor autoantibodies

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