Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence

Morris, Clive; Rosé, Alexandra; Curwen, Jon; Hughes, Andrew; Wilson, David J.; Webb, David J.

doi:10.1038/sj.bjc.6602676

Cited by 76 publications

(54 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More specific clinical data on this agent are limited. Phase 1 and 2 studies are under way with this compound in prostate cancer with little data on efficacy reported to date (44).…”

Section: Ets and Their Receptorsmentioning

confidence: 99%

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

Carducci

Jimeno

2006

Clinical Cancer Research

127

103

View full text Add to dashboard Cite

Recent advances in the understanding of prostate cancer biology and its progression to bone metastasis have led to the development of drugs directed against precise molecular alterations in the prostate tumor cell and host cells in the normal bone environment such as osteoclasts and osteoblasts. Endothelins (ETs) and their receptors have emerged as a potential target in prostate cancer bone metastasis. By activating the ET A receptor, ET-1is pathogenically involved in facilitating several aspects of prostate cancer progression, including proliferation, escape from apoptosis, invasion, and new bone formation, processes that are general to many malignancies. Notwithstanding, there are a number of features specifically driven by the ET axis in prostate cancer, such as creating and perpetuating a unique interaction between the metastatic prostate cancer cell and the bone microenvironment (osteoblast, osteoclast, and stroma) or altering the equilibrium in pain modulation. These features have led to the preferential clinical evaluation of atrasentan (ABT-627) as a biological therapy in prostate carcinoma, first in hormone-refractory prostate cancer. Biological activity of atrasentan in patients with prostate cancer has been shown by the suppression of biochemical markers of prostate cancer progression in bone, and clinical activity is evidenced by a consistent trend demonstrating a delay in time to disease progression when compared with placebo, especially in patients with bone metastases. Further studies of atrasentan and other selective ET-1antagonists (ZD4054) are ongoing.Recent advances in the understanding of prostate cancer biology and its progression to bone metastasis have led to the development of drugs directed against precise molecular alterations in the prostate tumor cell and host cells in the normal bone environment such as osteoclasts and osteoblasts. Targeting specific pathways to stop cancer growth is generally less toxic to normal cells and improves tolerability, and thus anticancer drug discovery has shifted from an empirical random screening approach to a more rational and mechanistic, target-directed approach, where specific abnormalities in cell functioning are modulated in a classic drug-receptor fashion (1). Endothelins (ETs) and their receptors have emerged as a potential target in prostate cancer bone metastasis and is the focus of this review. ETs and Their ReceptorsThe ETs constitute a family of three 21-amino-acid peptides (ET-1, ET-2, and ET-2) that are synthesized as propeptides and are transformed to their active forms by sequential endopeptidase-and ET-converting enzyme-mediated cleavage. ET-1 is the most common circulating form of ET and has a median half-life of 7 minutes (2). It is cleared by a double mechanism that consists in ET receptor B (ET B ) -mediated uptake and degradation by neutral endopeptidase (3). Each of the three ETs has a unique pattern of distribution; ET-1 is not organ specific and is expressed primarily by endothelial cells, whereas ET-2 is mainly presen...

show abstract

“…More specific clinical data on this agent are limited. Phase 1 and 2 studies are under way with this compound in prostate cancer with little data on efficacy reported to date (44).…”

Section: Ets and Their Receptorsmentioning

confidence: 99%

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

Carducci

Jimeno

2006

Clinical Cancer Research

127

103

View full text Add to dashboard Cite

show abstract

“…The recent identification of highly-selective small molecules that inhibit ligand-induced activation of ET A R offers the possibility of testing this therapeutic approach in a clinical setting (Remuzzi et al 2002). Among the ET A R antagonists, ZD4054 is an orally active ET A R antagonist in early clinical development for the treatment of cancer (Morris et al 2005). ABT-627 (Atrasentan) is an orally bioavailable endothelin antagonist that potently and selectively binds to the ET A R, blocking signal transduction pathways implicated in cancer, cell proliferation and other host-dependent processes promoting cancer growth (Carducci et al 2002(Carducci et al , 2003.…”

Section: Targeting Endothelin Receptor As Novel Approach In Ovarian Cmentioning

confidence: 99%

Emerging role of the endothelin axis in ovarian tumor progression

Bagnato¹,

Spinella²,

Rosanò³

2005

Endocr Relat Cancer

View full text Add to dashboard Cite

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ET A R and ET B R, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor-host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi's sarcoma, brain tumors and melanoma. Extensive experimental evidence links ET A R overexpression with tumor progression in ovarian cancer. ET A R engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ET A R signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ET A R mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial-mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ET A R by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ET A R in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ET A R. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ET A R blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.

show abstract

“…ZD4054 binds to the ET A R with high affinity. In preclinical studies, ZD4054 specifically antagonizes ET Amediated proliferative and antiapoptotic effects, but not ET B -mediated proapoptotic effects in different cell types (26,27). We have demonstrated previously that in ovarian cancer cells, ZD4054 antagonizes ET-1 -induced cell proliferation (27).…”

Section: Introductionmentioning

confidence: 99%

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Rosanò

Castro

Spinella

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The autocrine endothelin (ET)-1/endothelin A receptor (ET A R) pathway is an important regulator of several processes involved in ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET A R receptor as a potential target for improving ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of ZD4054, an orally active antagonist that specifically binds ET A R, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ET A Rpositive cell lines HEY, OVCA 433, SKOV-3, and A-2780, ZD4054 effectively inhibited the basal and ET-1 -induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. ZD4054 treatment also resulted in a reduction of ET A Rdriven angiogenesis and invasive mediators, such as vascular endothelial growth factor, cyclooxygenase-1/2, and matrix metalloproteinase (MMP). The combination of ZD4054 and paclitaxel led to the potentiation of all these effects, indicating that ZD4054, by blocking the ET A R-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to paclitaxel. In HEY ovarian cancer xenografts, ZD4054 significantly inhibited tumor growth to the same degree as paclitaxel. Furthermore, ZD4054-dependent tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of ZD4054 and paclitaxel produced additive antitumor effects, with 40% of mice remaining tumorfree, supporting a rationale for the clinical use of ZD4054 as monotherapy or in combination with cytotoxic drugs.

show abstract

Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence

Cited by 76 publications

References 23 publications

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

Emerging role of the endothelin axis in ovarian tumor progression

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Contact Info

Product

Resources

About