Somatostatin receptors in the diagnosis and treatment of thyroid cancer

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The current therapy for metastatic Hrthle cell thyroid carcinoma (HTC), radioactive iodine non-responsive papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC) does not result in long-lasting complete remissions or improved survival. The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer (TC). We showed that TC lesions have higher SSTR2 expression than normal thyroid. Further, we observed higher uptake of SST analog 68Ga-DOTA-TATE by positron emission tomography/computed tomography (PET/CT) in HTC patients in comparison to low-to-moderate uptake in PTC and MTC patients. Functional in vitro studies using human TC cell lines (TT, BCPAP, FTC133), and a rat pancreatic cell line with intrinsically high SSTR2 (AR42J), revealed that valproic acid (VAC) increases SSTR2 expression by regulating the acetylation of histone H3 and/or H4 at the SSTR2 promoter region. In vivo studies using mice xenografts demonstrated that diagnostic and therapeutic efficacy of SST analogs could be enhanced by utilizing radiolabeled DOTA-EB-TATE, which is characterized by significantly higher tumor uptake than DOTA-TATE (p<0.001) and DOTA-JR11 (p<0.001). Treatment with 177Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high SSTR2 tumor expression and high SST analogs uptake (AR42J) but had no effects in a model with low SSTR2low SST analogs uptake (FTC133). Overall, a novel SST analog, 177Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of TC patients characterized by high SST analogs uptake SSTR2 expression in metastatic lesions.