Novel therapies for the treatment of advanced prostate cancer

Abstract

In recent years, great success has been achieved on many fronts in the treatment of men with metastatic castration-resistant prostate cancer (CRPC), including novel chemotherapeutics, immunotherapies, bone microenvironment-targeted agents, and hormonal therapies. Numerous agents are currently in early-phase clinical trial development for the treatment of advanced prostate cancer. These novel therapies target several areas of prostate tumor biology, including the upregulation of androgen signaling and biosynthesis, critical oncogenic intracellular pathways, epigenetic alterations, and cancer immunology. Importantly, the characterization of the prostate cancer genome offers the potential to exploit conserved genetic alterations, which may increase the efficacy of these targeted therapies. Predictive and prognostic biomarkers are urgently needed to maximize therapeutic efficacy and safety of these promising new treatments options in prostate cancer.

Fig. 1

Intracellular signaling pathways involved in prostate cancer and opportunities for targeted therapies [12]. AR signaling is modulated by the MAPK, PI3K/AKT/mTOR, and b-catenin signaling pathways. Androgen directed agents: enzalutamide, Orteronel, ARN509, EPI509, Galeterone. Signal transduction inhibitors: cabozantinib, GDC-0068, MK2206, XL-147, BKM-120, dasatinib. The TMPRSS2:ETS fusion results in over expression of the ETS gene product which binds to the AR. Tumor suppressor gene transcription is regulated by epigenetic alterations including histone modification and CpG methylation. Epigenetic Alterations: Vorinostat, Pano-binostat, Azacitidine. EMT inhibition: Vismodegib (GDC-0449). Immune check point blockade: Ipilimumab, CT-011. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved.

Fig. 2

Frequency of select genetic alterations in CRPC exomes. AR Androgen receptor, APC adenomatous poliposis coli, ZFHX3 zinc finger homeobox 3, RB1 retinoblastoma 1, TP53 tumor protein 53, PTEN phosphatase and tensin homolog, BRCA2 breast cancer type 2 susceptibility. Data modified from Grasso et al. 2012 [1••].