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

Purpose: The impact of androgen receptor (AR) activity in breast cancer (BCa) biology is unclear. We characterized and tested a novel therapy to an AR-governed target in BCa. Experimental Design: We evaluated the expression of prototypical AR-gene products human kallikrein 2 (hK2) and Prostate Specific Antigen (PSA) in BCa models. We screened 13 well-characterized BCa cell lines for hK2 and PSA production upon in-vitro hormone stimulation by testosterone (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 (a)-particle emitting Actinium-225, to specifically treat AR-expressing BCa 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 BCa. AR activity in BCa 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 BCa a-emitter radiotherapy.

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