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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
ZD4054: a specific endothelin A receptor antagonist with promising activity in metastatic castration-resistant
1University of Wisconsin School of Medicine and Public Health, Health Sciences Learning Center, 750 Highland Avenue, Madison, WI 53705, USA.
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.
Insights
The endothelin A (ET(A)) receptor antagonist ZD4054 shows promise in prostate cancer treatment. Further clinical trials are planned to evaluate its efficacy in various stages of castrate-resistant prostate cancer.
Area of Science:
- Oncology
- Pharmacology
Background:
- Overexpression of the endothelin A (ET(A)) receptor is implicated in human cancer cell proliferation and survival.
- Endothelin-1 (ET-1) activates ET(A) receptors, promoting tumor growth, while ET(B) receptor activation has opposing effects.
- Targeting ET(A) may offer antitumor benefits while preserving ET(B)-mediated functions like apoptosis induction.
Purpose of the Study:
- To review the endothelin axis and the role of ET(A)/ET(B) receptors in prostate cancer malignancy.
- To assess the effects of the specific ET(A) antagonist ZD4054 in preclinical and clinical prostate cancer studies.
- To explore the clinical interest in ZD4054 for prostate cancer, considering ET-1's role in nociception and osteoblastic effects.
Main Methods:
- Review of existing data on the endothelin axis in cancer.
- Analysis of preclinical and clinical studies investigating ZD4054's effects.
- Examination of receptor-binding data for ZD4054 specificity to ET(A) over ET(B).
Main Results:
- ZD4054 is an orally bioavailable, specific ET(A) antagonist with no detected binding to ET(B).
- Prostate cancer exhibits increased ET(A) to ET(B) expression, correlating with higher tumor grade.
- Phase III trials are planned for ZD4054 in non-metastatic and metastatic castrate-resistant prostate cancer (CRPC).
Conclusions:
- Further investigation of ZD4054 in prostate cancer is warranted.
- Planned Phase III trials will assess ZD4054's efficacy in various CRPC patient groups.
- ZD4054's potential in combination therapy with docetaxel will also be evaluated.
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