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

Autor: Lugat A; Medical Oncology Department, Nantes University Hospital, 44000, Nantes, France.; Nuclear Medicine Department, Nantes University Hospital, 1, Place Alexis Ricordeau, 44000, Nantes, France.; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Chouin N; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Chocteau F; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Esnault M; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Marionneau-Lambot S; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Gouard S; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Frampas É; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France.; Central Department of Radiology and Medical Imaging, Nantes University Hospital, 44000, Nantes, France., Faivre-Chauvet A; Nuclear Medicine Department, Nantes University Hospital, 1, Place Alexis Ricordeau, 44000, Nantes, France.; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Bourgeois M; Nuclear Medicine Department, Nantes University Hospital, 1, Place Alexis Ricordeau, 44000, Nantes, France.; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Morgenstern A; European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany., Bruchertseifer F; European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany., Chérel M; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France.; Department of Nuclear Medicine, Institut de Cancérologie de L'Ouest (ICO) - Site Gauducheau, Saint-Herblain, France., Kraeber-Bodéré F; Nuclear Medicine Department, Nantes University Hospital, 1, Place Alexis Ricordeau, 44000, Nantes, France.; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Ansquer C; Nuclear Medicine Department, Nantes University Hospital, 1, Place Alexis Ricordeau, 44000, Nantes, France.; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France., Gaschet J; Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 8 Quai Moncousu, BP70721, Cedex 1, 44007, Nantes, France. joelle.gaschet@univ-nantes.fr.
Jazyk: angličtina
Zdroj: European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2024 Sep 13. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1007/s00259-024-06918-0
Abstrakt: Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [ 177 Lu]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 [ 225 Ac]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 [ 18 F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [ 225 Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [ 225 Ac]Ac-DOTATOC 10 days after intraportal graft.
Results: Liver tumors showed a high uptake of [ 68  Ga]Ga-DOTATOC and no uptake of [ 18 F]F-FDG confirming the well-differentiated phenotype. All groups treated with [ 225 Ac]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: [ 225 Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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