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13.09.2024 | Original Article

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

verfasst von: Alexandre Lugat, Nicolas Chouin, Florian Chocteau, Mathilde Esnault, Séverine Marionneau-Lambot, Sébastien Gouard, Éric Frampas, Alain Faivre-Chauvet, Mickaël Bourgeois, Alfred Morgenstern, Frank Bruchertseifer, Michel Chérel, Françoise Kraeber-Bodéré, Catherine Ansquer, Joëlle Gaschet

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 2/2025

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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.
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Metadaten
Titel
Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases
verfasst von
Alexandre Lugat
Nicolas Chouin
Florian Chocteau
Mathilde Esnault
Séverine Marionneau-Lambot
Sébastien Gouard
Éric Frampas
Alain Faivre-Chauvet
Mickaël Bourgeois
Alfred Morgenstern
Frank Bruchertseifer
Michel Chérel
Françoise Kraeber-Bodéré
Catherine Ansquer
Joëlle Gaschet
Publikationsdatum
13.09.2024
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 2/2025
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-024-06918-0