Novel therapeutic strategies for prostate cancer by inhibition

State-of-the-art therapies for metastatic prostate cancer include orchiectomy, gonadotropin-releasing hormone analogues, and anti-androgens bicalutamide and hydroxyflutamide. Patients initially respond to the therapy but eventually a refractory state develops within one to two years. A number of molecular mechanisms have been identified driving the progression to the castration-resistant phenotype:

• High Androgen Receptor (AR) expression and sensitivity through mRNA or protein stabilization or through amplification of the gene locus
• Mutation of the AR giving a broader ligand specificity to other steroids or even anti-androgens
• Activation of the AR through nonsteroidal factors such as growth factors and cytokines
• Overexpression of AR-coactivators
• Intratumoral synthesis of androgens
• Differential splicing resulting in AR variants that lack the ligand-binding domain and are constitutive active

These findings have contributed to the development of novel therapeutic strategies. Recently, abiraterone acetate has been approved as second-line therapy for prostate cancer patients that failed chemotherapy with docetaxel. Abiraterone acetate is a CYP17 inhibitor – an important enzyme in steroid synthesis – and significantly reduces androgen levels in the body. A novel anti-androgen is MDV 3100 which is currently undergoing clinical trials. It is able to block nuclear translocation of the AR and impairs binding to androgen response elements as well as interaction of AR with its coactivators. Another interesting molecule is EPI-001 that is targeting the N-terminal domain of the AR and thus may also inhibit AR variants that lack the C-terminal ligand-binding domain. We have recently investigated the potential of targeting AR coactivators. Using a siRNA approach we could show that the coactivator p300 is important in the survival and invasion pathways of prostate cancer cells. Inhibition of the p300 acetyltransferase domain by the small molecule inhibitor C646 similarly resulted in activation of apoptotic pathways. Hence, a number of different approaches that- in the end- target AR function have been investigated lately. However, their beneficial use for prostate cancer patients has to be demonstrated in practice.