Novel therapies for metastatic castrate-resistant prostate cancer

Abstract

Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.

Trial registration: ClinicalTrials.gov NCT00861614 NCT01057810.

Figures

Figure 1

The two-compartment model in bone for novel therapeutics in metastatic castrate-resistant prostate cancer. The “epithelial compartment” contains the prostate cancer epithelial cell (top). The “stromal compartment” contains multiple different cell types including osteoblasts, osteoclasts, T-cells, and endothelial cells (bottom). Multiple autocrine and paracrine signaling pathways that contribute to prostate cancer progression are depicted. The different novel therapeutics that target these pathways are also shown. Please refer to the body of the text for additional details. AR = androgen receptor; ETA-R = endothelin type A receptor; VEGF = vascular endothelial growth factor; DHT = dihydrotestosterone; GF-R = growth factor receptor.