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Preclinical Evaluation of a 177 Lu-Labeled Gastrin-Releasing Peptide Receptor Antagonist and Prostate Cancer Treatment with Monotherapy and in Combination with Everolimus

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide This study evaluates the potential of a 177 Lu-labeled GRPR-targeting antagonist as a radiotherapeutic agent for tumors expressing the gastrin-releasing peptide receptor (GRPR). The therapeutic effect of the radioligand was investigated both as a monotherapy and in combination with the mTOR inhibitor everolimus. The GRPR antagonist, LF1 (AAZTA 5 -Pip- d -Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ), was synthesized using the chelator AAZTA 5 linked via a 4-amino-1-carboxymethylpiperidine (Pip) spacer and radiolabeled with lutetium-177. The preclinical evaluation included assessments of binding kinetics, blood and organ clearance, plasma protein binding, and metabolic stability. SPECT/CT imaging and biodistribution studies were performed in mice bearing PC3 xenograft tumors. To assess its therapeutic efficacy, PC-3-mice were treated with [ 177 Lu]Lu-LF1 either alone or following everolimus pretreatment. [ 177 Lu]Lu-LF1 showed high binding affinity (K d = 0.12 ± 0.01 nM) and favorable pharmacokinetics, including rapid blood clearance and low plasma protein binding (2–3% at 5 and 15 min p.i.). Although subject to enzymatic degradation, the radioligand demonstrated high, sustained, and specific tumor uptake (42 ± 5.0% IA/g at 1 h and 3.9 ± 1.1% IA/g at 144 h p.i.). Pancreatic uptake cleared quickly, allowing for high-contrast SPECT/CT imaging. Therapeutically, tumors treated with 93 MBq of [ 177 Lu]Lu-LF1 grew more slowly than those treated with 41 MBq. The combination of everolimus and [ 177 Lu]Lu-LF1 resulted in significant tumor growth inhibition, compared to the relevant monotherapies with either [ 177 Lu]Lu-LF1 or everolimus. [ 177 Lu]Lu-LF1 shows promise as a therapeutic radioligand for GRPR-positive prostate cancer, offering high tumor uptake and rapid clearance from nontarget tissues. Mice bearing PC3 xenograft tumors were well tolerated and demonstrated enhanced therapeutic efficacy when combined with everolimus.

Source: ACS Pharmacology & Translational Science

DOI: 10.1021/acsptsci.5c00491