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

Thorek, Daniel L.J.; Ku, Anson T. LU ; Mitsiades, Nicholas; Veach, Darren; Watson, Philip A.; Metha, Dipti; Strand, Sven Erik LU ; Sharma, Sai Kiran; Lewis, Jason S. and Abou, Diane S., et al. (2019) In Clinical Cancer Research 25(2). p.881-891
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... (More)

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.

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Clinical Cancer Research
volume
25
issue
2
pages
11 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85060034378
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-18-1521
language
English
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yes
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31e604c6-4581-4747-8c45-1371ab11bc20
date added to LUP
2019-01-29 11:54:20
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2019-09-17 04:47:50
@article{31e604c6-4581-4747-8c45-1371ab11bc20,
  abstract     = {<p>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 &gt;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: [<sup>225</sup>Ac]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.</p>},
  author       = {Thorek, Daniel L.J. and Ku, Anson T. and Mitsiades, Nicholas and Veach, Darren and Watson, Philip A. and Metha, Dipti and Strand, Sven Erik and Sharma, Sai Kiran and Lewis, Jason S. and Abou, Diane S. and Lilja, Hans G. and Larson, Steven M. and McDevitt, Michael R. and Ulmert, David},
  issn         = {1078-0432},
  language     = {eng},
  number       = {2},
  pages        = {881--891},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-18-1521},
  volume       = {25},
  year         = {2019},
}