Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer Journal Article

Authors: Thorek, D. L. J.; Ku, A. T.; Mitsiades, N.; Veach, D.; Watson, P. A.; Metha, D.; Strand, S. E.; Sharma, S. K.; Lewis, J. S.; Abou, D. S.; Lilja, H. G.; Larson, S. M.; McDevitt, M. R.; Ulmert, D.
Article Title: Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer
Abstract: Purpose: The impact of androgen receptor (AR) activity Results: D-Norgestrel and DHT activated the AR pathway, in breast cancer biology is unclear. We characterized and while 17b-Estradiol did not. Competitive binding for AR tested a novel therapy to an AR-governed target in breast protein showed similar affinity between DHT and D-Norges-cancer. trel, indicating direct AR–ligand interaction. In vivo production Experimental Design: We evaluated the expression of of hK2 was sufficient to achieve site-specific delivery of ther-prototypical AR gene products human kallikrein 2 (hK2) apeutic radionuclide to tumor tissue at >20-fold over back- and PSA in breast cancer models. We screened 13 well-ground muscle uptake; effecting long-term local tumor characterized breast cancer cell lines for hK2 and PSA control. production upon in vitro hormone stimulation by testoster-Conclusions: [225Ac]hu11B6 targeted radiotherapy one [dihydrotestosterone (DHT)]. AR-positive lines were was potentiated by DHT and by D-Norgestrel in murine further evaluated by exposure to estrogen (17b-Estradiol) xenograft models of breast cancer. AR activity in and the synthetic progestin D-Norgestrel. We then evaluated breast cancer correlates with kallikrein-related peptidase-2 an anti-hK2–targeted radiotherapy platform (hu11B6), and can be activated by D-Norgestrel, a common con-labeled with alpha (a)-particle emitting Actinium-225, to traceptive, and AR induction can be harnessed for hK2-specifically treat AR-expressing breast cancer xenografts targeted breast cancer a-emitter radiotherapy. under hormone stimulation. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-01-15
Start Page: 881
End Page: 891
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1521
PUBMED: 30254080
PROVIDER: scopus
PMCID: PMC6524527
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Michael R Mcdevitt
    122 Mcdevitt
  2. Darren Veach
    64 Veach
  3. Hans Gosta Lilja
    307 Lilja
  4. Hans David Staffan Ulmert
    51 Ulmert
  5. Philip A Watson
    22 Watson
  6. Jason S Lewis
    313 Lewis
  7. Steven M Larson
    880 Larson
  8. Sai Kiran   Sharma
    18 Sharma
  9. Dipti   Mehta
    4 Mehta