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

Daniel L.J. Thorek; Anson T. Ku; Nicholas Mitsiades; Darren Veach; Philip A. Watson; Dipti Metha; Sven Erik Strand; Sai Kiran Sharma; Jason S. Lewis; Diane S. Abou; Hans G. Lilja; Steven M. Larson; Michael R. McDevitt; David Ulmert

doi:10.1158/1078-0432.CCR-18-1521

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

Daniel L.J. Thorek, Anson T. Ku, Nicholas Mitsiades, Darren Veach, Philip A. Watson, Dipti Metha, Sven Erik Strand, Sai Kiran Sharma, Jason S. Lewis, Diane S. Abou, Hans G. Lilja, Steven M. Larson, Michael R. McDevitt, David Ulmert

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17 Scopus citations

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: [ ²²⁵ 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.

Original language	English
Pages (from-to)	881-891
Number of pages	11
Journal	Clinical Cancer Research
Volume	25
Issue number	2
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-1521
State	Published - Jan 15 2019

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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. (2019). Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer. Clinical Cancer Research, 25(2), 881-891. https://doi.org/10.1158/1078-0432.CCR-18-1521

@article{3e938e4b97e942c79408070ea542fd0f,

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: [ 225 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.",

author = "Thorek, {Daniel L.J.} and Ku, {Anson T.} and Nicholas Mitsiades and Darren Veach and Watson, {Philip A.} and Dipti Metha 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 David Ulmert",

note = "Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2019",

month = jan,

day = "15",

doi = "10.1158/1078-0432.CCR-18-1521",

language = "English",

volume = "25",

pages = "881--891",

journal = "Clinical Cancer Research",

issn = "1078-0432",

number = "2",

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Thorek, DLJ, Ku, AT, Mitsiades, N, Veach, D, Watson, PA, Metha, D, Strand, SE, Sharma, SK, Lewis, JS, Abou, DS, Lilja, HG, Larson, SM, McDevitt, MR & Ulmert, D 2019, 'Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer', Clinical Cancer Research, vol. 25, no. 2, pp. 881-891. https://doi.org/10.1158/1078-0432.CCR-18-1521

TY - JOUR

T1 - Harnessing androgen receptor pathway activation for targeted alpha particle radioimmunotherapy of breast cancer

AU - Thorek, Daniel L.J.

AU - Ku, Anson T.

AU - Mitsiades, Nicholas

AU - Veach, Darren

AU - Watson, Philip A.

AU - Metha, Dipti

AU - Strand, Sven Erik

AU - Sharma, Sai Kiran

AU - Lewis, Jason S.

AU - Abou, Diane S.

AU - Lilja, Hans G.

AU - Larson, Steven M.

AU - McDevitt, Michael R.

AU - Ulmert, David

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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: [ 225 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.

AB - 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: [ 225 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.

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U2 - 10.1158/1078-0432.CCR-18-1521

DO - 10.1158/1078-0432.CCR-18-1521

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SN - 1078-0432

VL - 25

SP - 881

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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ER -

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

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