Novel therapeutic approaches for the treatment of castration-resistant prostate cancer

Abstract

Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.

Keywords: AR; Androgen receptor; Bone metastasis angiogenesis; CRPC; Castration-resistant prostate cancer; Chemotherapy; ET; Growth factor receptor inhibitors; IGF; Immunotherapy; OS; PCa; PDGFR; PFS; PSA; RANK ligand; RANK-L; Radiotherapy; SD; TKI; VEGF; VEGFR; androgen receptor; castration-resistant prostate cancer; endothelin; insulin-like growth factor; overall survival; platelet-derived growth factor receptor; progression free survival; prostate cancer; prostate-specific antigen; stable disease; tyrosine kinase inhibitor; vascular endothelial growth factor; vascular endothelial growth factor receptor.

Fig. 1

Monitoring of prostate cancer, therapy efficacy and tumor progression. Several methods are used for assessment of PCa spread, monitoring of therapy responses and determining of disease progression (right panel). The Computer tomography images (left panel) show the metastatic sites (white arrows) of patients with advanced prostate cancer.

Fig. 2

Schematic overview on new therapeutic agents for castration resistant prostate cancer (CRPC) and their targets. In metastatic CRPC testicular androgen supply is blocked by androgen deprivation therapy through chemical or surgical castration. Tumor cells (PCa) rely on the supply of weak androgen hormones from the adrenal gland, which are converted to testosterone and dihydrothestosterone (DHT) through P450 cytochrome 17,20 lyase (CYP17A) and 5α-reductase (5αRed). The androgen receptor (AR), which is often overexpressed and or mutated is activated by hormones, gain of function mutations and crosstalk with growth receptor signaling pathways and transported to the nucleus where it binds to genomic AR binding sites and initiates formation of a transcription complex and regulates genes expression. Bone is the preferred site of metastasis of prostate cancer. Prostate cancer cells release cytokines, protease and regulators to manipulate the cells in their environment (fibroblasts, osteoclasts, osteoblasts), induce angiogenesis and degrade extracellular matrix compounds (ECM) and release growth factors and compounds supporting tumor cell growth, survival and metabolism. Growth factors activate their receptors on the surface of the tumor cells to trigger intracellular signaling cascades that enhance metabolism, cell cycle progression and survival signals either directly or through stimulation of transcription factors (TF) in the nucleus. Additional players at the metastatic sites are infiltrating lymphocytes and other cells of the immune system, especially cytotoxic T-cells, which attack tumor cells. Symbols: —>, stimulation or release; —|; inhibition; , therapeutic stimulation; , therapeutic inhibition.