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
{"title":"胰腺神经内分泌肿瘤肝脏微转移临床前模型中的[225Ac]Ac-DOTATOC alpha疗法对生存的影响","authors":"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","doi":"10.1007/s00259-024-06918-0","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [<sup>177</sup>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 [<sup>225</sup>Ac]Ac-DOTATOC in an original preclinical murine model simulating the development of well-characterized liver metastases of pancreatic NETs with SSTR overexpression.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [<sup>68</sup> Ga]Ga-DOTATOC and [<sup>18</sup>F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [<sup>225</sup>Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [<sup>225</sup>Ac]Ac-DOTATOC 10 days after intraportal graft.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Liver tumors showed a high uptake of [<sup>68</sup> Ga]Ga-DOTATOC and no uptake of [<sup>18</sup>F]F-FDG confirming the well-differentiated phenotype. All groups treated with [<sup>225</sup>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 (<i>p</i> = 0.0001), and 58 days with 2 × 120 kBq (<i>p</i> < 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.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>[<sup>225</sup>Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.</p>","PeriodicalId":11909,"journal":{"name":"European Journal of Nuclear Medicine and Molecular Imaging","volume":null,"pages":null},"PeriodicalIF":8.6000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases\",\"authors\":\"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\",\"doi\":\"10.1007/s00259-024-06918-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Abstract</h3><p>Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [<sup>177</sup>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 [<sup>225</sup>Ac]Ac-DOTATOC in an original preclinical murine model simulating the development of well-characterized liver metastases of pancreatic NETs with SSTR overexpression.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [<sup>68</sup> Ga]Ga-DOTATOC and [<sup>18</sup>F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [<sup>225</sup>Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [<sup>225</sup>Ac]Ac-DOTATOC 10 days after intraportal graft.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>Liver tumors showed a high uptake of [<sup>68</sup> Ga]Ga-DOTATOC and no uptake of [<sup>18</sup>F]F-FDG confirming the well-differentiated phenotype. All groups treated with [<sup>225</sup>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 (<i>p</i> = 0.0001), and 58 days with 2 × 120 kBq (<i>p</i> < 0.0001) vs 28 days with non-radiolabeled DOTATOC. 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Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases
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.
期刊介绍：
The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.
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