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 sst2 antagonists are better tools to target neuroendocrine tumors (NET) than sst2 agonists. Indeed, antagonists bind to a greater number of sst2 sites than agonists. Whether sst2 antagonists could be used successfully to target non-NET tumors, expressing low sst2 density, is unknown. Here, we compare quantitatively ¹²⁵I-JR11 sst2 antagonist binding in vitro with that of the sst2 agonist ¹²⁵I-Tyr3-octreotide in large varieties of non-NET and NET. Methods: In vitro receptor autoradiography was performed with ¹²⁵I-JR11 and ¹²⁵I-Tyr3-octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues, as well as NETs as reference. Results: In general, ¹²⁵I-JR11 binds to many more sst2 sites than ¹²⁵I-Tyr3-octreotide. In 13 breast cancers, 8 have low binding (mean density: 844±168 dpm/mg tissue) with the agonist while 12 have a high binding (mean density: 4447±1128 dpm/mg tissue) with the antagonist. All 12 renal cell cancers (RCC) show a low binding of sst2 with the agonist (mean density: 348±49 dpm/mg tissue) while all cases have a very high sst2 binding with the antagonist (mean density: 3777±582 dpm/mg tissue). 1/5 medullary thyroid cancers are positive with the agonist, while 5/5 are positive with the antagonist. In 15 Non-Hodgkin lymphomas (NHL), many more sst2 sites are labelled with the antagonist than with the agonist. In 14 prostate cancers, none have sst2 binding with the agonist and only 4 have a weak binding with the antagonist. None of 17 colon cancers show sst2 sites with the agonist and only 3 cases are weakly positive with the antagonist. In the various tumor types, adjacent sst2-expressing tissues such as vessels, lymphocytes, nerves, mucosa or stroma were more strongly labelled 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 sst2 sites measured with the antagonist. Conclusion: All RCC, a majority of breast cancers, NHL and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst2 by sst2 antagonists, comparable to NET radiotargeting with sst2 agonists.