Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer.

Abstract

PURPOSE:

The 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.

RESULTS:

D-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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 2 Pg. 881-891 (01 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30254080 (Publication Type: Journal Article)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Immunoconjugates
• Receptors, Androgen
• HK2 protein, human
• Hexokinase

Topics

• Alpha Particles (therapeutic use)
• Animals
• Biomarkers, Tumor
• Breast Neoplasms (metabolism, mortality, pathology, therapy)
• Cell Line, Tumor
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Female
• Hexokinase (antagonists & inhibitors)
• Humans
• Immunoconjugates (administration & dosage, pharmacokinetics)
• Mice
• Molecular Targeted Therapy
• Radioimmunotherapy
• Radiometry
• Receptors, Androgen (metabolism)
• Signal Transduction (drug effects, radiation effects)
• Tissue Distribution
• Xenograft Model Antitumor Assays