Castration Determines the Efficacy of ETAR Blockade in a Mouse Model of Prostate Cancer Bone Metastasis

Abstract

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 (ETAR), located on osteoblasts, reduce osteoblastic bone lesions in animal models of bone metastasis. However, ETAR 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, ETAR 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 ETAR 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 ETAR and androgen signaling, whereby ETAR blockade was most efficacious when combined with complete androgen deprivation.

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Among these, IGF1 activates phosphoinositide 3-kinase (PI3K)/Akt mammalian target of rapamycin (mTOR) pathway, with subsequent breast cancer cell growth, proliferation, and migration into the bone [17,61,62]. Osteoblasts can also be regulated by metastatic tumor cell-derived factors including endothelin 1 (ET1), dickkopf 1 (DKK1), and the Wnt signaling cascade [36,[63][64][65][66]. While Wnt promotes osteoblast differentiation, its activity can be inhibited by DKK1, which is an antagonist in this cascade.…”

Biological and Clinical Aspects of Metastatic Spinal Tumors

“…However, a placebo-controlled phase III trial showed the ineffectiveness of atrasentan in delaying the progression of bone metastatic lesions in castrate-resistant prostate cancer [ 230 ]. Interestingly, a preclinical study on zibotentan demonstrated that the effectiveness of that endothelin A inhibitor considerably depends on androgen ablation [ 231 ].…”

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

“…These data, together with results from other solid tumors, make the use of ET axis inhibitors a promising approach toward PCa progression and metastasis. Although, in a recent meta-analysis, the use of ET-A receptor antagonists with or without docetaxel was not proven to offer improvement in survival or disease progression for CRPC, other recent data suggest that ET-A blockade is most efficacious when combined with complete androgen deprivation for the control of bone metastases [ 186 , 187 ].…”