Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177Lu‐DOTAGA‐PEG2‐RM26. Issue 12 (23rd May 2019)

• Record Type: Journal Article
• Authors: Mitran, Bogdan; Rinne, Sara S.; Konijnenberg, Mark W.; Maina, Theodosia; Nock, Berthold A.; Altai, Mohamed; Vorobyeva, Anzhelika; Larhed, Mats; Tolmachev, Vladimir; de Jong, Marion; Rosenström, Ulrika; Orlova, Anna
• Is Part Of: International journal of cancer. Volume 145:Issue 12(2019)
• Page Start: 3347
• Page End: 3358
• Publication Date: 2019-05-23
• Subjects: radionuclide therapy -- GRPR -- HER2 -- prostate cancer -- lutetium‐177; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32401
• Languages: English
• ISSNs: 0020-7136

Abstract

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 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‐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 (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‐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 177 Lu‐labeled PEG2 ‐RM26 analogs, we concluded that 177 Lu‐DOTAGA‐PEG2 ‐RM26 was the most promising analog 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. Abstract : What's new? Targeted radionuclide therapy (TRT) using radiolabeled peptides seeking gastrin‐releasing peptide receptors (GRPRs) in tumors is a promising approach to treat disseminated prostate cancer. The possibility to improve the therapeutic index via combination therapies also warrants further investigation. Here, the authors developed and characterized a promising GRPR‐targeting radioligand and demonstrated its therapeutic efficacy in prostate cancer xenografts. Moreover, this study using the anti‐HER2 antibody trastuzumab presents the first in vivo proof‐of‐principle that the effects of anti‐GRPR radiotherapy can be amplified by co‐administration of anti‐HER2 treatment leading to prolonged survival.