Highly Increased ¹²⁵I-JR11 Antagonist Binding In Vitro Reveals Novel Indications for sst₂ Targeting in Human Cancers

Abstract

There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst 2 ) antagonists are better tools to target neuroendocrine tumors (NETs) than sst 2 agonists. Indeed, antagonists bind to a greater number of sst 2 sites than agonists. Whether sst 2 antagonists could be used successfully to target non-NETs, expressing low sst 2 density, is unknown. Here, we compare quantitatively 125 I-JR11 sst 2 antagonist binding in vitro with that of the sst 2 agonist 125 I-Tyr 3 -octreotide in large varieties of non-NET and NET. Methods: In vitro receptor autoradiography was performed with 125 I-JR11 and 125 I-Tyr 3 -octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues as well as NETs as reference. Results: In general, 125 I-JR11 binds to many more sst 2 sites than 125 I-Tyr 3 -octreotide. In 13 breast cancers, 8 had a low binding (mean density, 844 6 168 dpm/mg of tissue) with the agonist whereas 12 had a high binding (mean density, 4,447 6 1,128 dpm/mg of tissue) with the antagonist. All 12 renal cell cancers showed a low binding of sst 2 with the agonist (mean density, 348 6 49 dpm/mg of tissue) whereas all cases had a high sst 2 binding with the antagonist (mean density, 3,777 6 582 dpm/mg of tissue). One of 5 medullary thyroid cancers was positive with the agonist, whereas 5 of 5 were positive with the antagonist. In 15 nonHodgkin lymphomas, many more sst 2 sites were labeled with the antagonist than with the agonist. In 14 prostate cancers, none had sst 2 binding with the agonist and only 4 had a weak binding with the antagonist. None of 17 colon cancers showed sst 2 sites with the agonist, and only 3 cases were weakly positive with the antagonist. In the various tumor types, adjacent sst 2 -expressing tissues such as vessels, lymphocytes, nerves, mucosa, or stroma were more strongly labeled with the antagonist than with the agonist. The reference NET cases, incubated with a smaller amount of tracer, were also found to have many more sst 2 sites measured with the antagonist. Conclusion: All renal cell cancers and most breast cancers, non-Hodgkin lymphomas, and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst 2 by sst 2 antagonists, comparable to NET radiotargeting with sst 2 agonists. Somat ostatin receptors (sst) are highly overexpressed in gastroenteropancreatic and extra-gastrointestinal neuroendocrine tumors (NETs). This represents the molecular basis for sst-targeted diagnostic and therapeutic procedures in NET patients with somatostatin analogs (1-3). One main clinical application makes use of the inhibitory effects of somatostatin on NET cells, particularly on hormone secretion: long-acting somatostatin analogs, such as octreotide or lanreotide, potently inhibit tumoral hormone secretion and improve related symptoms. The second targeting approach is based on the administration of radioactive somatostatin analogs for diagnostic or therapeutic purposes. Indeed, 111 In-octreotide scintigraphy (OctreoScan; Mal...

Somatostatin Receptor Antagonists for Imaging and Therapy

“…About 60 human tissue samples from different tumors were analyzed by in vitro receptor autoradiography to compare the binding capacities of 125 I-JR11 (sstr2 antagonist) and 125 I-Tyr 3 -octreotide (sstr2 agonist) in successive tissue sections. The sstr2-binding affinities (IC 50 s) of both 125 I-labeled tracers were similar (20). Both radioligands efficiently bound to sstr2 in different tumor tissues.…”

“…The better performance of radiolabeled sstr antagonists than of agonists was also impressively demonstrated with human tumor specimens (20). About 60 human tissue samples from different tumors were analyzed by in vitro receptor autoradiography to compare the binding capacities of 125 I-JR11 (sstr2 antagonist) and 125 I-Tyr 3 -octreotide (sstr2 agonist) in successive tissue sections.…”

Design and development of the theranostic pair 177Lu‐OPS201/68Ga‐OPS202 for targeting somatostatin receptor expressing tumors

“…The inherent ability of sstr antagonists to recognize more binding sites compared with agonists in NETs and other tumor entities, supports their utilization in tumors with lower sstr density (non‐NET indications), such as breast and small‐cell lung cancer. This opens the way to a theranostic approach in indications that are not among those diagnosed or treated with radiolabeled somatostatin analogs so far.…”

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

“…Also, somatostatin receptors have been shown previously to be present in breast cancers, however, in relatively low amounts (23,24). A recently conducted study in vitro with an iodinated somatostatin receptor antagonist revealed, however, that a large amount of sst 2 could be detected in more than 90% of breast cancers (25).…”