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Trastuzumab co-treatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177 Lu-DOTAGA-PEG2 -RM26.
Int J Cancer. 2019 May 11;:
Authors: Mitran B, Rinne SS, Konijnenberg MW, Maina T, Nock BA, Altai M, Vorobyeva A, Larhed M, Tolmachev V, de Jong M, Rosenström U, Orlova A
Abstract
Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2 -RM26 for labeling with 177 Lu and further determined the effect of treatment with 177 Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in a murine model. The PEG2 -RM26 analogue was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-conjugates were labeled with 177 Lu and characterized in vitro and in vivo. A pre-clinical therapeutic study was performed in PC-3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2 -RM26, (C) 177 Lu-DOTAGA-PEG2 -RM26, (D) trastuzumab, or (E) 177 Lu-DOTAGA-PEG2 -RM26 in combination with trastuzumab. 177 Lu-DOTAGA-PEG2 -RM26 demonstrated quantitative labeling yield at high molar activity (0.3 MBq/pmol), high in vivo stability (5 min pi >98% of radioligand remained when co-injected with phosphoramidon), high affinity to GRPR (KD =0.4±0.2 nM), and favourable biodistribution (1 h pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177 Lu-DOTAGA-PEG2 -RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (C 66 d, E >70 d). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment-related toxicity was observed. Based on in vitro and in vivo characterization of the four 177 Lu-labeled PEG2 -RM26 analogues we concluded that 177 Lu-DOTAGA-PEG2 -RM26 was the most promising analogue for TRT. Radiotherapy using 177 Lu-DOTAGA-PEG2 -RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti-HER2 therapy additionally improved survival. This article is protected by copyright. All rights reserved.
Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2 -RM26 for labeling with 177 Lu and further determined the effect of treatment with 177 Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in a murine model. The PEG2 -RM26 analogue was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-conjugates were labeled with 177 Lu and characterized in vitro and in vivo. A pre-clinical therapeutic study was performed in PC-3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2 -RM26, (C) 177 Lu-DOTAGA-PEG2 -RM26, (D) trastuzumab, or (E) 177 Lu-DOTAGA-PEG2 -RM26 in combination with trastuzumab. 177 Lu-DOTAGA-PEG2 -RM26 demonstrated quantitative labeling yield at high molar activity (0.3 MBq/pmol), high in vivo stability (5 min pi >98% of radioligand remained when co-injected with phosphoramidon), high affinity to GRPR (KD =0.4±0.2 nM), and favourable biodistribution (1 h pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177 Lu-DOTAGA-PEG2 -RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (C 66 d, E >70 d). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment-related toxicity was observed. Based on in vitro and in vivo characterization of the four 177 Lu-labeled PEG2 -RM26 analogues we concluded that 177 Lu-DOTAGA-PEG2 -RM26 was the most promising analogue for TRT. Radiotherapy using 177 Lu-DOTAGA-PEG2 -RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti-HER2 therapy additionally improved survival. This article is protected by copyright. All rights reserved.
PMID: 31077356 [PubMed - as supplied by publisher]
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