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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 (17?-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2-targeted radiotherapy platform (hu11B6), labeled with alpha (?)-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 17?-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 ?-emitter radiotherapy.

SUBMITTER: Thorek DLJ

PROVIDER: S-EPMC6524527 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Thorek Daniel L J DLJ Ku Anson T AT Mitsiades Nicholas N Veach Darren D Watson Philip A PA Metha Dipti D Strand Sven-Erik SE Sharma Sai Kiran SK Lewis Jason S JS Abou Diane S DS Lilja Hans G HG Larson Steven M SM McDevitt Michael R MR Ulmert David D

Clinical cancer research : an official journal of the American Association for Cancer Research 20180925 2

<h4>Purpose</h4>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.<b>Experimental Design:</b> 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 <i>in vitro</i> hormone stimulation by testosterone [dihydrotestosterone (DHT ...[more]

PMID: 30254080

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Project description:BACKGROUND:Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values?<?.001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo. METHODS:The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer. RESULTS:A 44-year-old white woman with metastatic breast cancer who was estrogen receptor-positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in (18)F-FDG PET/CT and (18)F-NaF bone PET/CT. The patient derived clinical benefit from therapy. CONCLUSION:We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA-approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.

Dataset Information

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

Publications

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

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