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Open AccessArticle

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model

1
Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway
2
Bayer AG, Pharmaceuticals Division, Berlin 13353, Germany
3
Bayer AG, Pharmaceuticals Division, Wuppertal 42113, Germany
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(4), 155; https://doi.org/10.3390/ph12040155
Received: 18 September 2019 / Revised: 11 October 2019 / Accepted: 12 October 2019 / Published: 15 October 2019
Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers. View Full-Text
Keywords: targeted Thorium-227 conjugate; HER2-TTC; DNA damage response; Thorium-227; targeted alpha therapy targeted Thorium-227 conjugate; HER2-TTC; DNA damage response; Thorium-227; targeted alpha therapy
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Wickstroem, K.; Karlsson, J.; Ellingsen, C.; Cruciani, V.; Kristian, A.; Hagemann, U.B.; Bjerke, R.M.; Ryan, O.B.; Linden, L.; Mumberg, D.; Brands, M.; Cuthbertson, A. Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model. Pharmaceuticals 2019, 12, 155.

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