1. Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer
- Author
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Thorek, Daniel LJ, Ku, Anson T, Mitsiades, Nicholas, Veach, Darren, Watson, Philip A, Metha, Dipti, Strand, Sven-Erik, Sharma, Sai Kiran, Lewis, Jason S, Abou, Diane S, Lilja, Hans G, Larson, Steven M, McDevitt, Michael R, and Ulmert, David
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Biotechnology ,Breast Cancer ,Estrogen ,2.1 Biological and endogenous factors ,Aetiology ,Alpha Particles ,Animals ,Biomarkers ,Tumor ,Breast Neoplasms ,Cell Line ,Tumor ,Disease Models ,Animal ,Dose-Response Relationship ,Drug ,Dose-Response Relationship ,Radiation ,Female ,Hexokinase ,Humans ,Immunoconjugates ,Mice ,Molecular Targeted Therapy ,Radioimmunotherapy ,Radiometry ,Receptors ,Androgen ,Signal Transduction ,Tissue Distribution ,Xenograft Model Antitumor Assays ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeThe impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer.Experimental Design: We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models. We screened 13 well-characterized breast cancer cell lines for hK2 and PSA production upon in vitro hormone stimulation by testosterone [dihydrotestosterone (DHT)]. AR-positive lines were further evaluated by exposure to estrogen (17β-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2-targeted radiotherapy platform (hu11B6), labeled with alpha (α)-particle emitting Actinium-225, to specifically treat AR-expressing breast cancer xenografts under hormone stimulation.ResultsD-Norgestrel and DHT activated the AR pathway, while 17β-Estradiol did not. Competitive binding for AR protein showed similar affinity between DHT and D-Norgestrel, indicating direct AR-ligand interaction. In vivo production of hK2 was sufficient to achieve site-specific delivery of therapeutic radionuclide to tumor tissue at >20-fold over background muscle uptake; effecting long-term local tumor control.Conclusions[225Ac]hu11B6 targeted radiotherapy was potentiated by DHT and by D-Norgestrel in murine xenograft models of breast cancer. AR activity in breast cancer correlates with kallikrein-related peptidase-2 and can be activated by D-Norgestrel, a common contraceptive, and AR induction can be harnessed for hK2-targeted breast cancer α-emitter radiotherapy.
- Published
- 2019