Novel non-AR therapeutic targets in castrate resistant prostate cancer

Abstract

Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.

Keywords: Androgen receptor (AR); abiraterone; castrate resistant prostate cancer (CRPC); non-AR therapeutic targets.

Figure 1

Current targets in castrate-resistant prostate cancer according to targeted cancer hallmarks. Adapted from Hanahan et al. Weinberg [2011]. PI3K, phosphoinositol triphosphate kinase; CTLA4, cytotoxic T-lymphocyte antigen 4; PD1, programmed cell death protein 1; AMPK, adenosine monophosphate-activated protein kinase; VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; PARP, poly-ADP ribose polymerase.

Figure 2

Schematic of the c-MET pathway. Adapted from Loriot et al. (35). ERK, extracellular related kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositol triphosphate kinase.

Figure 3

Schematic of the PI3K/Akt pathway. mTOR, mammalian target of rapamycin; PTEN, Phosphatase and tensin homolog; NFκβ, nuclear factor kappa beta; PI3K, phosphoinositol triphosphate kinase.