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 ETA receptor, ET-1 is 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-1 antagonists (ZD4054) are ongoing.