Experimental radiotherapy with the gastrin-releasing peptide receptor (GRPR) antagonist [¹⁷⁷Lu]Lu-AU-SAR-M1 in a...

The gastrin-releasing peptide receptor (GRPR) is highly expressed in prostate and breast cancers and hence serves as a legitimate target for radionuclide therapy (TRT). Radiolabeled GRPR antagonists are attractive radionuclide-carriers for TRT, due to their rapid tissue penetration, fast blood/whole-body clearance and inherent biosafety. We hereby explore the impact of dosing frequency of a GRPR-radioantagonist with improved tumor retention on therapeutic efficacy. For this purpose, we first studied the biodistribution of the recently developed [¹⁷⁷Lu]Lu-AU-SAR-M1 in mice to estimate dosimetry. Next, mice with PC-3 xenografts (GRPR-positive) were treated with 6 injections of [¹⁷⁷Lu]Lu-AU-SAR-M1 (12 MBq/injection), administered weekly (Group 1) or in 2 cycles of 3 injections/week with a 4-week interval (Group 2); an additional Control group got vehicle injections. Body weight, tumor volume, and blood cell counts were monitored. No evidence of bone marrow toxicity was observed. Both treatment regimens significantly slowed down tumor growth and improved survival. Median survival in the Control group was 37 d, while 50% of tumors were eradicated in the treated groups (no significant difference between groups). These preclinical findings qualify [¹⁷⁷Lu]Lu-AU-SAR-M1, as a promising candidate for TRT in patients. Results of this study might be used in the design of follow-up studies.