Differentiated thyroid cancer (DTC) is the most frequent endocrine tumor with a good prognosis after primary treatment in most cases. By contrast, 30-40% of patients with metastatic DTC are... Show moreDifferentiated thyroid cancer (DTC) is the most frequent endocrine tumor with a good prognosis after primary treatment in most cases. By contrast, 30-40% of patients with metastatic DTC are unresponsive to I-131 radioactive iodide (RAI) treatment due to tumor dedifferentiation. Currently, underlying molecular mechanisms of dedifferentiation remain elusive and predictive biomarkers are lacking. Therefore, the present study aimed to identify molecular biomarkers in primary tumors associated with RAI refractoriness. A retrospective cohort was gathered consisting of RAI-sensitive patients with DTC and RAI-refractory patients with poorly DTC. In all patients, extensive intratumoral mutation profiling, gene fusions analysis, telomerase reverse transcriptase (TERT) promoter mutation analysis and formalin-fixed paraffin-embedded-compatible RNA sequencing were performed. Genetic analyses revealed an increased mutational load in RAI-refractory DTC, including mutations in AKT1, PTEN, TP53 and TERT promoter. Transcriptomic analyses revealed profound differential expression of insulin-like growth factor 2 (IGF2), with up to 100-fold higher expression in RAI-refractory DTC compared with in RAI-sensitive DTC cases. ELISA revealed significant lower IGF2 plasma concentrations after surgery and subsequent I-131 RAI therapy in patients with DTC compared with pretreatment baseline. Overall, the current findings suggested that the tumor-promoting growth factor IGF2 may have a potential role in acquiring RAI refractoriness. Show less
A subgroup of patients with thyroid cancer (10-15% of patients with DTC) with distant metastases have high remission rates after conventional RaI-treatment. We have explored several routes which in... Show moreA subgroup of patients with thyroid cancer (10-15% of patients with DTC) with distant metastases have high remission rates after conventional RaI-treatment. We have explored several routes which in time may help to improve the prognosis for this subset of patients, focussing on the TSHR. The combination of troglitazone and lovastatin may have potential use in DTC as we observed a strong reduction of growth and distinct changes in morphology in the follicular thyroid carcinoma cell-line FTC-133 at clinically achievable concentrations. Furthermore, the combination of troglitazone and lovastatin was able to increase the expression of NIS and the TSHR which may prove to be beneficial in sensitizing thyroid tumor cells to conventional RaI therapy. Secondly, we explored the possibility of thyroid specific membrane associated therapy by using the TSHR as a target. We succeeded in modifying TSH into a potential vehicle for toxins by converting it into a single chain protein with improved binding to the TSHR. The fusion of short proteins to our modified single chain TSH did not impair binding thus confirming the potential in using modified TSH as a vehicle for therapeutic proteins. We have demonstrated in our studies that a balanced attitude is feasible in commonly used TSH suppressing thyroxine replacement therapy, thus preventing those patients from the potential negative effects of long term TSH suppression on other organs. Show less