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Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177 Lu‐DOTAGA‐PEG 2 ‐RM26
Author(s) -
Mitran Bogdan,
Rinne Sara S.,
Konijnenberg Mark W.,
Maina Theodosia,
Nock Berthold A.,
Altai Mohamed,
Vorobyeva Anzhelika,
Larhed Mats,
Tolmachev Vladimir,
Jong Marion,
Rosenström Ulrika,
Orlova Anna
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32401
Subject(s) - trastuzumab , in vivo , biodistribution , bombesin , radionuclide therapy , peg ratio , medicine , pharmacology , chemistry , prostate cancer , in vitro , cancer , receptor , biochemistry , biology , microbiology and biotechnology , neuropeptide , breast cancer , finance , economics
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 PEG 2 ‐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 PEG 2 ‐RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide‐chelator conjugates were labeled with 177 Lu and characterized in vitro and in vivo . A preclinical therapeutic study was performed in PC‐3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA‐PEG 2 ‐RM26, (C) 177 Lu‐DOTAGA‐PEG 2 ‐RM26, (D) trastuzumab or (E) 177 Lu‐DOTAGA‐PEG 2 ‐RM26 in combination with trastuzumab. 177 Lu‐DOTAGA‐PEG 2 ‐RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% of radioligand remained when coinjected with phosphoramidon), high affinity to GRPR ( K D = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177 Lu‐DOTAGA‐PEG 2 ‐RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment‐related toxicity was observed. In conclusion, based on in vitro and in vivo characterization of the four 177 Lu‐labeled PEG 2 ‐RM26 analogs, we concluded that 177 Lu‐DOTAGA‐PEG 2 ‐RM26 was the most promising analog for TRT. Radiotherapy using 177 Lu‐DOTAGA‐PEG 2 ‐RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti‐HER2 therapy additionally improved survival.