Comparison of the therapeutic response to treatment with a 177-lutetium labeled somatostatin receptor agonist and antagonist in preclinical models

Peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) agonists are successfully being applied in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic anti-tumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of ¹⁷⁷Lu-DOTA-octreotate, an SSTR agonist, and ¹⁷⁷Lu-DOTA-JR11, an SSTR antagonist. Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double strand breaks, by determining the number of p53 binding protein 1 (53BP1) foci, after incubating SSTR2 positive cells with ¹⁷⁷Lu-DTPA, ¹⁷⁷Lu-DOTA-octreotate or ¹⁷⁷Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor xenografted mice to determine the optimal dose for therapy experiments. Afterwards in vivo therapy experiments comparing the effect of ¹⁷⁷Lu-DOTA-octreotate and ¹⁷⁷Lu-DOTA-JR11 were performed in this same animal model. Results: We found a 5 times higher uptake of ¹⁷⁷Lu-DOTA-JR11 compared to that of ¹⁷⁷Lu-DOTA-octreotate. The major part (88±1%) of the antagonist uptake was membrane bound, while 74±3% of the total receptor agonist uptake was internalized. Cells treated with ¹⁷⁷Lu-DOTA-JR11 showed 2 times more 53BP1 foci compared to cells treated with ¹⁷⁷Lu-DOTA-octreotate. Biodistribution studies with ¹⁷⁷Lu-DOTA-JR11 (0.5 μg/30 MBq) resulted in the highest tumor radiation dose of 1.8±0.7 Gy/MBq, 4.4 times higher than the highest tumor radiation dose found for ¹⁷⁷Lu-DOTA-octreotate. In vivo therapy studies with ¹⁷⁷Lu-DOTA-octreotate and ¹⁷⁷Lu-DOTA-JR11 resulted in a tumor growth delay time of 18±5 d and 26±7 d, respectively. Median survival rates were 43.5 d, 61 d and 71 d for the control group, the ¹⁷⁷Lu-DOTA-octreotate and the ¹⁷⁷Lu-DOTA-JR11 treated group, respectively. Conclusion: Based on these results we conclude that the use of radiolabeled SSTR antagonists such as JR11 might enhance PRS and PRRT of neuroendocrine tumors and provide successful imaging and therapeutic strategies for cancer types with relatively low SSTR expression.

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