Endothelin Receptor Antagonism: A Novel Therapeutic Option in Castration-Resistant Prostate Cancer

REVIEW ARTICLE


Michael Borre

Affiliation: Department of Urology, Aarhus University Hospital, Skejby, Denmark

ABSTRACT

Treatment with chemotherapy results in limited therapeutic and quality of life improvements in patients with castration-resistant prostate cancer (CRPC), and new efficacious and well-tolerated therapies are needed to more effectively treat this disease, before resorting to the use of cytotoxic agents. The endothelin (ET) axis, which comprises ET-1, ET-2, ET-3 and the ETA and ETB receptors, performs important physiological functions, as a modulator of vasomotor tone, and in tissue differentiation, cell proliferation and hormone production. The role of the endothelin system has also been investigated in malignant disease, and the ET-1/ETA interaction has been implicated in the growth and progression of a variety of tumours. Subsequently, novel therapeutic interventions have been developed that inhibit ETA receptor interactions. A broad range of data is available on the impact of ETA receptor antagonists in a number of urological, gynaecological and breast cancers. The clinical investigations of the selective ETA receptor antagonist atrasentan in prostate cancer have shown promise. Antitumour activity, control of metastatic bone involvement and reductions in cancer-associated pain have all been documented. However, significant improvements in time to progression and overall survival have not been demonstrated. Preliminary clinical data from trials investigating the specific ETA receptor antagonist zibotentan are encouraging, and a promising overall survival signal has been achieved, despite non-significant effects on progression-free survival. A large Phase 3 programme currently ongoing with this agent should further define the role of ETA receptor antagonists in treating CRPC.

Keywords: Atrasentan, clinical trial, endothelin, endothelin receptor antagonist, metastasis, prostate cancer, zibotentan

Correspondence: Michael Borre, Department of Urology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. Tel: + 45 8949 5909; Fax: + 45 89 49 6006; e-mail: borre@ki.au.dk