Endothelin and Skeletal Metastases in Hormone-Refractory Prostate Cancer

Abstract

Skeletal metastases represent a major complication of advanced hormone-refractory prostate cancer (HRPC). These lesions affect around 85% of patients and provide a poor quality of life due to associated pathological fractures, spinal compression and pain. Metastatic HRPC is incurable and typically fatal within 2 years of diagnosis. At present, there is no effective treatment for delaying disease progression. Current treatment options based on chemotherapy, radiotherapy and bisphosphonates are essentially palliative and do not appear to prolong survival. HRPC, therefore, represents a considerable unmet clinical need, and new therapies are required to alter the course of the disease process beyond providing palliation. Many factors are involved in bone remodelling, and a substantial body of evidence suggests a major role for endothelin-1 (ET-1) in the pathophysiology of bone lesions in metastatic HRPC. In HRPC, the binding of ET-1 to a specific receptor (ET A) not only enhances osteoblastic activity and promotes the development of metastatic bone lesions, but also generates a mitogenic and anti-apoptotic milieu. In vivo and in vitro studies show that ET-1-stimulated bone growth is inhibited when the ET-1 receptor (ET A) is blocked. Highly potent and specific ET A-receptor antagonists, therefore, represent an exciting development in the management of HRPC, providing a potentially effective therapeutic target for the delay or prevention of skeletal metastatic progression.