SUN-118 Somatostatin Agonist Conjugated to the Evans Blue Moiety Is a Superior Analog in the Diagnosis and Treatment of Tumors Characterized by High Somatostatin Receptor Expression

Abstract

Background: Radiolabeled somatostatin (SST) analogs have been proven to be effective in the diagnosis and treatment of neuroendocrine tumors (NETs), which are characterized by high somatostatin receptor (SSTR2) expression. At present, there are several SST analogs available that differ from each other in the affinity for SSTR2 and tumor retention time. To date, only a single SST agonist -DOTA-TATE- has been approved by the FDA for imaging and treatment of NETs. Recent studies have shown that addition of Evans blue (EB) moiety to an SST agonist results in superior uptake and increased retention time within the tumors. The goal of our study was to compare the diagnostic and therapeutic efficacy of three different radiolabeled SST analogs in a tumor mice model: EB-TATE - a novel modified agonist; DOTA-TATE - an agonist and JR11 - an antagonist. Methods: A rat pancreatic cell line (AR42J), characterized by high SSTR2 expression, was used to create a subcutaneous xenograft mice model. The AR42J cells formed sizable tumors within two weeks post-injection. The 86Y-EB-TATE, 68Ga-DOTA-TATE, and 68Ga-DOTA-JR11 were used to determine standard uptake values by positron emission tomography (PET) imaging. For treatment purposes, the SST analogs were labeled with 177Lu to generate 177Lu-EB-TATE, 177Lu-DOTA-TATE and 177Lu-DOTA-JR11. The mice were assigned to treatment groups based on comparable tumor volume at baseline and received two doses (0.5mCi) of the 177Lu-labeled analogs one week apart. Tumor measurements were performed twice per week and the mice were euthanized if their tumor burden exceeded 2 cm at any point in the study or after 6 weeks - landmark of the end of the study. Results: Among the three analogs tested, the novel SST analog 86Y-EB-TATE was characterized by 4.3- and 3.7- fold higher tumor uptake in comparison to 68Ga-DOTA-TATE (p<0.001) and 68Ga-DOTA-JR11 (p<0.001), respectively. There was no significant difference between the uptake of 68Ga-DOTA-TATE and 68Ga-DOTA-JR11 (p=0.9). Consistently with higher tumor uptake on imaging, 177Lu-EB-TATE-treated mice responded to the treatment with an overall 86.5±13.2% reduction in the tumor volume after two weeks post-therapy. On the contrary, despite therapy with 177Lu-DOTA-TATE and 177Lu-DOTA-JR11, the mice treated with these agents presented with tumor progression exceeding 2 cm and were euthanized. Consequently, the progression-free survival (PFS) was significantly longer in 177Lu-EB-TATE group (24±0 days) compared with 177Lu-DOTA-TATE (7.7±2.6 days, p<0.001) and 177Lu-DOTA-JR11 (6.3±3 days, p<0.001). There was no difference in PFS between 177Lu-DOTA-TATE and 177Lu-DOTA-JR11-treated mice (p=0.3). Conclusion: EB-TATE is characterized by superior diagnostic and therapeutic efficacy in comparison to DOTA-TATE and DOTA-JR11. EB-TATE might be used as imaging and therapeutic agent in tumors characterized by high SSTR2 expression.