177Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer

Purpose: 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 through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues. Experimental Design: We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUVmax) of SSTR2 analogue, Ga-68-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional in vitro studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy in vivo. Results: Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest Ga-68-DOTA-TATE uptake [median SUVmax, 16.5 (7.9-29)] than other types of thyroid cancers. In vivo studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE (P < 0.001) and DOTA-JR11 (P < 0.001). Treatment with Lu-177-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUVmax, 15.16 +/- 4.34), but had no effects in a model with low SST analogues uptake (SUVmax, 4.8 +/- 0.27). Conclusions: A novel SST analogue, Lu-177-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.