Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

Abstract

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...

Metastasis: a therapeutic target for cancer

“…72 Overall, atrasentan was well tolerated and delayed the progression of hormone-refractory prostate cancer in some men. 73 One of the trials reported a separate pharmaco dynamic analysis of biological end points that included changes in bone deposition markers such as total alkaline phosphatase, bone alkaline phosphatase and the bone resorption markers N-telopeptides, C-telopeptides and deoxy pyridinoline. 74 Analysis revealed that mean changes from baseline in total alkaline phosphatase, bone alkaline phosphatase and deoxy pyridinoline were consistently lower in patients receiving 10 mg atrasentan than in patients receiving placebo.…”

ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole

“…Accordingly, selective ET A R antagonism inhibits ET-1-mediated induction of MMPs and the uPA/PAI system [2,3,12]. In breast cancer cells, the pro-invasive effect of ET-1 could be a result of interactions between ET A R downstream cascades and HIF-1α signalling: as previously shown in melanoma and ovarian cancer cells, ET-1 via HIF-1α activation induces pro-invasive factors [2,40].…”

“…ZD4054 inhibits proliferation of ovarian carcinoma cells and tumour growth in vivo [6], enhances paclitaxel efficacy [10] and exhibits improved antitumoural activity when combined with EGFR inhibitor gefitinib [11]. In prostate cancer, ZD4054 has been evaluated for its efficacy on bone metastases in hormone-refractory prostate cancer (HRPC) [3,12].…”

Homing of Cancer Cells to the Bone

“…Endothelins (ETs) and their receptors have emerged as a potential target in prostate cancer bone metastasis. ET-1 antagonists such as atrasentan (ABT-627) and ZD4054 are currently being clinically evaluated as a biological therapy for prostate cancer bone metastasis [185]. PSK1404, an antagonist of α5β3 integrin significantly inhibits bone metastasis in animal models of metastatic breast and ovarian cancer [186].…”