PMID- 32255671
OWN - NLM
STAT- MEDLINE
DCOM- 20210510
LR  - 20210510
IS  - 1557-8852 (Electronic)
IS  - 1084-9785 (Print)
IS  - 1084-9785 (Linking)
VI  - 35
IP  - 7
DP  - 2020 Sep
TI  - Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality 
      in Targeted Alpha Therapy.
PG  - 497-510
LID - 10.1089/cbr.2020.3568 [doi]
AB  - Targeted alpha therapy (TAT) offers the potential for the targeted delivery of potent 
      alpha-particle-emitting radionuclides that emit high linear energy transfer 
      radiation. This leads to a densely ionizing radiation track over a short path. 
      Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA 
      double-strand breaks (DSBs). To date, radium-223 ((223)Ra) is the only TAT 
      approved for the treatment of patients with metastatic castration-resistant 
      prostate cancer. Thorium-227 ((227)Th), the progenitor nuclide of (223)Ra, offers 
      promise as a wider-ranging alternative due to the availability of efficient 
      chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO 
      chelator can be readily conjugated to a range of targeting moieties, enabling the 
      generation of new targeted thorium-227 conjugates (TTCs). This review provides a 
      comprehensive overview of the advances in the preclinical development of TTCs for 
      hematological cancers, including CD22-positive B cell cancers and CD33-positive 
      leukemia, as well as for solid tumors overexpressing renal cell cancer antigen 
      CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, 
      prostate-specific membrane antigen in prostate cancer, and fibroblast growth 
      factor receptor 2. As the mechanism of action for TTCs is linked to the formation 
      of DSBs, the authors also report data supporting combinations of TTCs with 
      inhibitors of the DNA damage response pathways, including those of the ataxia 
      telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, 
      emerging evidence suggests that TTCs induce immunogenic cell death through the 
      release of danger-associated molecular patterns. Based on encouraging preclinical 
      data, clinical studies have been initiated to investigate the safety and 
      tolerability of TTCs in patients with various cancers.
FAU - Hagemann, Urs B
AU  - Hagemann UB
AD  - Bayer AG, Berlin, Germany.
FAU - Wickstroem, Katrine
AU  - Wickstroem K
AD  - Bayer AS, Oslo, Norway.
FAU - Hammer, Stefanie
AU  - Hammer S
AD  - Bayer AG, Berlin, Germany.
FAU - Bjerke, Roger M
AU  - Bjerke RM
AD  - Bayer AS, Oslo, Norway.
FAU - Zitzmann-Kolbe, Sabine
AU  - Zitzmann-Kolbe S
AD  - Bayer AG, Berlin, Germany.
FAU - Ryan, Olav B
AU  - Ryan OB
AD  - Bayer AS, Oslo, Norway.
FAU - Karlsson, Jenny
AU  - Karlsson J
AD  - Bayer AS, Oslo, Norway.
FAU - Scholz, Arne
AU  - Scholz A
AD  - Bayer AG, Berlin, Germany.
FAU - Hennekes, Hartwig
AU  - Hennekes H
AD  - Bayer AG, Berlin, Germany.
FAU - Mumberg, Dominik
AU  - Mumberg D
AD  - Bayer AG, Berlin, Germany.
FAU - Cuthbertson, Alan S
AU  - Cuthbertson AS
AD  - Bayer AS, Oslo, Norway.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20200407
PL  - United States
TA  - Cancer Biother Radiopharm
JT  - Cancer biotherapy & radiopharmaceuticals
JID - 9605408
RN  - 0 (3,2-hydroxypyridinone)
RN  - 0 (Alarmins)
RN  - 0 (Chelating Agents)
RN  - 0 (Immunoconjugates)
RN  - 0 (Pyridones)
RN  - 0 (Radiopharmaceuticals)
RN  - 0 (Thorium-227)
RN  - 60YU5MIG9W (Thorium)
SB  - IM
MH  - Alarmins/metabolism
MH  - Alpha Particles/*therapeutic use
MH  - Chelating Agents/chemistry
MH  - DNA Damage/radiation effects
MH  - Hematologic Neoplasms/genetics/immunology/pathology/*radiotherapy
MH  - Humans
MH  - Immunoconjugates/chemistry/*therapeutic use
MH  - Immunogenic Cell Death/radiation effects
MH  - Precision Medicine/methods
MH  - Pyridones/chemistry
MH  - Radiopharmaceuticals/chemistry/pharmacology/*therapeutic use
MH  - Thorium/chemistry/pharmacology/*therapeutic use
MH  - Treatment Outcome
PMC - PMC7475103
OTO - NOTNLM
OT  - 227Th
OT  - conjugate
OT  - precision oncology
OT  - targeted alpha therapy
COIS- All are employees of Bayer.
EDAT- 2020/04/08 06:00
MHDA- 2021/05/11 06:00
PMCR- 2020/08/31
CRDT- 2020/04/08 06:00
PHST- 2020/04/08 06:00 [pubmed]
PHST- 2021/05/11 06:00 [medline]
PHST- 2020/04/08 06:00 [entrez]
PHST- 2020/08/31 00:00 [pmc-release]
AID - 10.1089/cbr.2020.3568 [pii]
AID - 10.1089/cbr.2020.3568 [doi]
PST - ppublish
SO  - Cancer Biother Radiopharm. 2020 Sep;35(7):497-510. doi: 10.1089/cbr.2020.3568. 
      Epub 2020 Apr 7.