Castration Determines the Efficacy of E[T.sub.A]R Blockade in a Mouse Model of Prostate Cancer Bone Metastasis

Bone metastasis is a painful complication of advanced prostate cancer. Endothelin-1 is a tumor-secreted factor that plays a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2019-08, Vol.160 (8), p.1786
Main Authors: Moon, Henry H, Clines, Katrina L, Cooks, Mark A, Cialek, Charlotte A, Esvelt, Marian A, Clines, Gregory A
Format: Article
Language:English
Subjects:
Bone cancer
Care and treatment
Castration
Cell receptors
Endothelin
Health aspects
Hormone antagonists
Metastasis
Patient outcomes
Prostate cancer
Testing
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Summary:Bone metastasis is a painful complication of advanced prostate cancer. Endothelin-1 is a tumor-secreted factor that plays a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor (E[T.sub.A]R), located on osteoblasts, reduce osteoblastic bone lesions in animal models of bone metastasis. However, E[T.sub.A]R antagonists demonstrated limited efficacy in clinical trials of men with advanced prostate cancer who also received standard androgen deprivation therapy (ADT). Previous data from our group suggested that, in a mouse model, E[T.sub.A]R antagonists might only be efficacious when androgen signaling in the osteoblast is lowered beyond the ability of standard ADT. This notion was tested in a mouse model of prostate cancer bone metastasis. Castrated and sham-operated male athymic nude mice underwent intracardiac inoculation of the ARCaPM castration-resistant prostate cancer cell line. The mice were then treated with either the E[T.sub.A]R antagonist zibotentan or a vehicle control to generate four experimental groups: vehicle+sham (Veh+Sham), vehicle+castrate (Veh+Castr), zibotentan+sham (Zibo+Sham), and zibotentan+castrate (Zibo+Castr). The mice were monitored radiographically for the development of skeletal lesions. The Zibo+Castr group had significantly longer survival and a single incidental lesion. Mice in the Zibo+Sham group had the shortest survival and the largest number of skeletal lesions. Survival and skeletal lesions of the Veh+Sham and Veh+Castr groups were intermediate compared with the zibotentan-treated groups. We report a complex interaction between E[T.sub.A]R and androgen signaling, whereby E[T.sub.A]R blockade was most efficacious when combined with complete androgen deprivation. (Endocrinology 160: 1786-1796, 2019)
ISSN:0013-7227
DOI:10.1210/en.2019-00261