PMID- 31618864
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 1424-8247 (Print)
IS  - 1424-8247 (Electronic)
IS  - 1424-8247 (Linking)
VI  - 12
IP  - 4
DP  - 2019 Oct 15
TI  - Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with 
      Olaparib in a BRCA2 Deficient Xenograft Model.
LID - 10.3390/ph12040155 [doi]
LID - 155
AB  - 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.
FAU - Wickstroem, Katrine
AU  - Wickstroem K
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      katrine.wickstroem@bayer.com.
FAU - Karlsson, Jenny
AU  - Karlsson J
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      jenny.karlsson@bayer.com.
FAU - Ellingsen, Christine
AU  - Ellingsen C
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      christine.ellingsen@bayer.com.
FAU - Cruciani, Veronique
AU  - Cruciani V
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      veronique.cruciani@bayer.com.
FAU - Kristian, Alexander
AU  - Kristian A
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      alexander.kristian@bayer.com.
FAU - Hagemann, Urs B
AU  - Hagemann UB
AD  - Bayer AG, Pharmaceuticals Division, Berlin 13353, Germany. 
      urs.hagemann@bayer.com.
FAU - Bjerke, Roger M
AU  - Bjerke RM
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. roger.bjerke@bayer.com.
FAU - Ryan, Olav B
AU  - Ryan OB
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. olav.ryan@bayer.com.
FAU - Linden, Lars
AU  - Linden L
AD  - Bayer AG, Pharmaceuticals Division, Wuppertal 42113, Germany. 
      lars.linden@bayer.com.
FAU - Mumberg, Dominik
AU  - Mumberg D
AD  - Bayer AG, Pharmaceuticals Division, Berlin 13353, Germany. 
      dominik.mumberg@bayer.com.
FAU - Brands, Michael
AU  - Brands M
AD  - Bayer AG, Pharmaceuticals Division, Berlin 13353, Germany. 
      michael.brands@bayer.com.
FAU - Cuthbertson, Alan
AU  - Cuthbertson A
AD  - Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway. 
      alan.cuthbertson@bayer.com.
LA  - eng
GR  - 246531/030/Research Council of Norway/
PT  - Journal Article
DEP - 20191015
PL  - Switzerland
TA  - Pharmaceuticals (Basel)
JT  - Pharmaceuticals (Basel, Switzerland)
JID - 101238453
PMC - PMC6958469
OTO - NOTNLM
OT  - DNA damage response
OT  - HER2-TTC
OT  - Thorium-227
OT  - targeted Thorium-227 conjugate
OT  - targeted alpha therapy
COIS- All authors are employed by Bayer AS or Bayer AG. No other potential conflicts of 
      interest relevant to this article exist. Lars Linden, Dominik Mumberg, and 
      Michael Brands are shareholders of Bayer Ag.
EDAT- 2019/10/18 06:00
MHDA- 2019/10/18 06:01
PMCR- 2019/12/01
CRDT- 2019/10/18 06:00
PHST- 2019/09/18 00:00 [received]
PHST- 2019/10/11 00:00 [revised]
PHST- 2019/10/12 00:00 [accepted]
PHST- 2019/10/18 06:00 [entrez]
PHST- 2019/10/18 06:00 [pubmed]
PHST- 2019/10/18 06:01 [medline]
PHST- 2019/12/01 00:00 [pmc-release]
AID - ph12040155 [pii]
AID - pharmaceuticals-12-00155 [pii]
AID - 10.3390/ph12040155 [doi]
PST - epublish
SO  - Pharmaceuticals (Basel). 2019 Oct 15;12(4):155. doi: 10.3390/ph12040155.