ZD4054: a specific endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer

Abstract

Background: Overexpression of the endothelin A (ETA) receptor has been found in a number of human cancer cell lines. Activation of the ETA receptor by endothelin-1 (ET-1) promotes cell proliferation and survival in these tumors, whereas activation of the endothelin B (ETB) receptor results in an opposing effect. Therefore, blockade of ETA may have antitumor effects, while sparing ETB-mediated effects such as induction of apoptosis and clearance of ET-1. Objective: ZD4054 is an orally bioavailable, specific ETA antagonist currently being investigated in prostate cancer. In receptor-binding studies, ZD4054 only bound to ETA, with no binding detected towards ETB. Prostate cancer cell lines are known to produce ET-1 and there is a relative increase in expression of ETA to ETB in these cancers. There is also an association of greater ETA expression in higher grade versus lower grade tumors, suggesting that ETA may be involved in the malignant transformation process. As ET-1 may also mediate nociceptive effects and osteoblastic effects, there is much interest in clinically assessing ZD4054 in prostate cancer. Methods: The data describing the endothelin axis, the role of ETA and ETB in malignancy, and the effects of ETA antagonist ZD4054 in prostate cancer, as demonstrated in preclinical and clinical studies, are reviewed. Results: Further investigation of ZD4054 in prostate cancer is warranted, and Phase III trials are already planned in patients with non-metastatic castrate-resistant prostate cancer (CRPC) with rising prostate specific antigen values, metastatic (asymptomatic) CRPC, and in metastatic CRPC in combination with docetaxel, assessing either differences in progression-free survival and overall survival or overall survival alone.