Abstract
Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.
Highlights
Neuroblastoma (NB) is the most common extracranial childhood malignancy, responsible for 15% of all childhood cancer deaths [1]
This study has allowed us to demonstrate the association between somatostatin receptor-2 (SSTR2) expression and 68Ga-DOTA-TATE uptake, which potentially leads to the antitumor activity of 177LuDOTA-TATE in NB preclinical models
Histological colocalization of SSTR2 and 68Ga-DOTA-TATE was observed in our study
Summary
Neuroblastoma (NB) is the most common extracranial childhood malignancy, responsible for 15% of all childhood cancer deaths [1]. Despite intensive treatment protocols including multimodal therapy with hematopoietic stem cell transplantation and immunotherapy, three-year disease-free survival is only about 60% for metastatic disease compared to 95% for localized tumors [2, 3]. Somatostatin receptors (SSTRs) are expressed at relatively low levels in most organs. They are moderately expressed in the brain, gastrointestinal tract, pancreas, kidney, and spleen. SSTRs, especially SSTR2, have been shown to be highly expressed in various human tumors including pancreatic, small cell lung, and carcinoid tumors, as well as paraganglioma, pheochromocytoma, and neuroblastoma [4]. Georgantzi et al demonstrated variable frequencies of somatostatin receptor (SSTR1-5) expression in 5 NB cell lines and 11 NB patient tumor biopsy samples [5], making molecular imaging and radionuclide therapy with somatostatinbased nuclear probes an attractive therapeutic option in appropriately selected patient populations [6]
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