Integrating Molecular Oncology into Therapeutic Strategies for Prostate Cancer

Context: Prostate cancer (PCa) is the most common cancer and the second leading cause of death from cancer in males in most Western countries. Advanced PCa is initially sensitive to androgen-deprivation therapy (ADT) but eventually progresses to castration resistance. Most treatments of PCa currently available are based on either cytotoxicity directed against tumour cells (chemotherapy) or targeting the androgen receptor directly or indirectly. Objective: Targeting agents have recently been developed to treat a variety of cancers. New and promising targets have been identified, and new agents targeting these molecules are currently being studied in patients with PCa. Some of these major potential targets are reviewed in this article. Recent data on a selection of new targets and new targeting agents are summarised in this review. The androgen receptor axis is active in the setting of castration-resistant prostate cancer (CRPC), and subsequent hormonemanipulation therapy showed anticancer activity using agents such as abiraterone or new-generation androgen receptor inhibitors. Another treatment strategy to consider is the use of targeted therapy to directly treat bone metastases. Several bone-targeting agents are currently in development, including ZD4054, which targets the endothelin type A receptor; denosumab, which targets the Rank-ligand axis; and the combination of docetaxel-based chemotherapy with samarium-153, a radiopharmaceutical agent. Moreover, a large number of other biological targets have been identified, and clinical trials are ongoing in a variety of PCa settings to test drugs targeting angiogenesis, proliferation, and apoptosis. A number of large randomized phase 3 trials are ongoing in patients with metastatic CRPC, and first results are awaited in 2009-2010. Conclusion: With the identification of new, promising biological targets and the availability of potentially active and well-tolerated targeting agents, most patients with CRPC should be offered participation in clinical trials and should be referred to centres in which these trials are available.