Purpose Non-medullary thyroid cancer (NMTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). However, in a subset of NMTC patients tumor... Show morePurpose Non-medullary thyroid cancer (NMTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). However, in a subset of NMTC patients tumor dedifferentiation occurs, leading to RAI resistance. Digoxin has been demonstrated to restore iodide uptake capacity in vitro in poorly differentiated and anaplastic NMTC cells, termed redifferentiation. The aim of the present study was to investigate the in vivo effects of digoxin in TPO-Cre/LSL-Braf(V600E) mice and digoxin-treated NMTC patients. Methods Mice with thyroid cancer were subjected to 3D ultrasound for monitoring tumor growth and I-124 PET/CT for measurement of intratumoral iodide uptake. Post-mortem analyses on tumor tissues comprised gene expression profiling and measurement of intratumoral autophagy activity. Through PALGA (Dutch Pathology Registry), archived tumor material was obtained from 11 non-anaplastic NMTC patients who were using digoxin. Clinical characteristics and tumor material of these patients were compared to 11 matched control NMTC patients never treated with digoxin. Results We found that in mice, tumor growth was inhibited and I-124 accumulation was sustainably increased after short-course digoxin treatment. Post-mortem analyses revealed that digoxin treatment increased autophagy activity and enhanced expression of thyroid-specific genes in mouse tumors compared to vehicle-treated mice. Digoxin-treated NMTC patients exhibited significantly higher autophagy activity and a higher differentiation status as compared to matched control NMTC patients, and were associated with favourable clinical outcome. Conclusions These in vivo data support the hypothesis that digoxin may represent a repositioned adjunctive treatment modality that suppresses tumor growth and improves RAI sensitivity in patients with RAI-refractory NMTC. 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
