Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26

Bogdan Mitran, Sara S. Rinne, Mark W. Konijnenberg, Theodosia Maina, Berthold A. Nock, Mohamed Altai, Anzhelika Vorobyeva, Mats Larhed, Vladimir Tolmachev, Marion de Jong, Ulrika Rosenström, Anna Orlova

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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 177Lu and further determined the effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in a murine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelator conjugates were labeled with 177Lu 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-PEG2-RM26, (C) 177Lu-DOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-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 (KD = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGA-PEG2-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 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog for TRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti-HER2 therapy additionally improved survival.

Original languageEnglish
Pages (from-to)3347-3358
Number of pages12
JournalInternational Journal of Cancer
Volume145
Issue number12
DOIs
Publication statusPublished - 15 Dec 2019
Externally publishedYes

Keywords

  • GRPR
  • HER2
  • lutetium-177
  • prostate cancer
  • radionuclide therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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