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. 2025 Jan;52(2):730-743.
doi: 10.1007/s00259-024-06918-0. Epub 2024 Sep 13.

Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases

Alexandre Lugat  1   2   3 , Nicolas Chouin  3 , Florian Chocteau  3 , Mathilde Esnault  3 , Séverine Marionneau-Lambot  3 , Sébastien Gouard  3 , Éric Frampas  3   4 , Alain Faivre-Chauvet  2   3 , Mickaël Bourgeois  2   3 , Alfred Morgenstern  5 , Frank Bruchertseifer  5 , Michel Chérel  3   6 , Françoise Kraeber-Bodéré #  2   3 , Catherine Ansquer #  2   3 , Joëlle Gaschet #  7
Affiliations

Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases

Alexandre Lugat et al. Eur J Nucl Med Mol Imaging. 2025 Jan.

Abstract

Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [177Lu]Lu-DOTATATE has shown a good clinical efficacy in neuroendocrine tumors (NETs), most of the patients only achieved tumoral stabilization and rare but severe long-term hematological toxicities have been reported. One of the promising options to improve PRRT is targeted alpha therapy. It is therefore essential to propose animal models that can mimic systemic spread disease, especially microscopic disease such as early stage of NET liver metastases to explore targeted alpha therapy. Herein, we report the evaluation of efficacy and toxicity of [225Ac]Ac-DOTATOC in an original preclinical murine model simulating the development of well-characterized liver metastases of pancreatic NETs with SSTR overexpression.

Methods: A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [68 Ga]Ga-DOTATOC and [18F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [225Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [225Ac]Ac-DOTATOC 10 days after intraportal graft.

Results: Liver tumors showed a high uptake of [68 Ga]Ga-DOTATOC and no uptake of [18F]F-FDG confirming the well-differentiated phenotype. All groups treated with [225Ac]Ac-DOTATOC showed a significant increase in overall survival compared with DOTATOC-treated mice, especially those treated with the highest activities: 53 days with 240 kBq (p = 0.0001), and 58 days with 2 × 120 kBq (p < 0.0001) vs 28 days with non-radiolabeled DOTATOC. On blood tests, a transient and moderate decreased in white blood cells count after treatment and no severe hepatic or renal toxicity were observed after treatment which was consistent with pathological and radiation dosimetry findings.

Conclusion: [225Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.

Keywords: Actinium-225; Neuroendocrine tumor; PET/MRI; Somatostatin analogs; Targeted alpha therapy.

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Conflict of interest statement

Declarations. Research involving animals: All animal experiments were carried out in accordance with the European directive 2010/63/EU on the protection of laboratory animals and its transposition into French law (decree n 2013–118) and were conducted on the Experimental Therapeutic Unit platform (SFR François Bonamy, IRS-UN, University of Nantes, license number: D44-278). Informed consent: Not applicable. Conflicts of interest: No potential conflicts of interest relevant to this article exist.

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