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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • Washington University in St. Louis
  • Baylor College of Medicine
  • Memorial Sloan-Kettering Cancer Center
  • Skåne University Hospital
  • University of Oxford
  • Jonsson Comprehensive Cancer Center
  • University of California, Los Angeles
  • Cornell University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)881-891
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number2
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes