Journal Article

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Haller, Stephanie, Rodriguez, Josep M. Monné, Borgna, Francesca, van der Meulen, Nicholas P., Köster, Ulli, Schibli, Roger, Müller, Cristina, Ginj, Mihaela, Grundler, Pascal V., Zeevaart, Jan Rijn

2022

Overview

Purpose The β ¯ -emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the 161 Tb- and 177 Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [ 161 Tb]Tb-DOTA-LM3 was 102-fold more potent than [ 177 Lu]Lu-DOTA-LM3; however, 161 Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177 Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [ 161 Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [ 177 Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [ 161 Tb]Tb-DOTA-LM3 may outperform the clinically employed [ 177 Lu]Lu-DOTATOC for the treatment of patients with NENs.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer Verlag (Germany) [1976-....]
• Subject: Animals / Augers / Cardiology / Cell membranes / Cell viability / Cytoplasm / Electrons / Humans / Imaging / Lutetium / Lutetium isotopes / Medicine / Medicine & Public Health / Mice / Neoplasia / Neoplasms / Neuroendocrine tumors / Neuroendocrine Tumors - pathology / Nuclear Medicine / Octreotide / Oncology / Original / Original Article / Orthopedics / Physics / Radioisotopes / Radiology / Radiopharmacy / Receptors / Receptors, Somatostatin - metabolism / Somatostatin / Somatostatin receptors / Survival / Terbium / Terbium - therapeutic use / Tissue Distribution / Tumor cells / Tumors