ZD4054: a specific endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer.
BACKGROUND
Overexpression of the endothelin A (ET(A)) receptor has been found in a number of human cancer cell lines. Activation of the ET(A) receptor by endothelin-1 (ET-1) promotes cell proliferation and survival in these tumors, whereas activation of the endothelin B (ET(B)) receptor results in an opposing effect. Therefore, blockade of ET(A) may have antitumor effects, while sparing ET(B)-mediated effects such as induction of apoptosis and clearance of ET-1.


OBJECTIVE
ZD4054 is an orally bioavailable, specific ET(A) antagonist currently being investigated in prostate cancer. In receptor-binding studies, ZD4054 only bound to ET(A), with no binding detected towards ET(B). Prostate cancer cell lines are known to produce ET-1 and there is a relative increase in expression of ET(A) to ET(B) in these cancers. There is also an association of greater ET(A) expression in higher grade versus lower grade tumors, suggesting that ET(A) 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 ET(A) and ET(B) in malignancy, and the effects of ET(A) 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.
Warren
Ruth
R
University of Wisconsin School of Medicine and Public Health, Health Sciences Learning Center, 750 Highland Avenue, Madison, WI 53705, USA.
Liu
Glenn
G
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D008297:Male; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D044022:Receptor, Endothelin A / Q000096:biosynthesis
D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C511404:ZD4054