Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

Abstract

Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.

Differential Expression of a Panel of Ten CNTN1-Associated Genes during Prostate Cancer Progression and the Predictive Properties of the Panel towards Prostate Cancer Relapse

“…Metastatic PCs (mPCs) are commonly managed with androgen deprivation therapy (ADT); resistance nonetheless commonly develops in the form of castration-resistant PC (CRPC) [ 11 , 12 ]. Although multiple therapeutic options are available for CRPCs, including taxane-based chemotherapy [ 13 ], AR-targeting therapy involving either abiraterone or enzalutamide [ 12 , 14 , 15 , 16 ], and immunotherapy [ 17 , 18 ], effective control of CRPC remains the major challenge [ 12 , 19 , 20 ]. This reflects the complex mechanisms underlying PC progression.…”

High Antiproliferative Activity of Hydroxythiopyridones over Hydroxypyridones and Their Organoruthenium Complexes

“…HDAC inhibitors attenuate acetylation events and block several cancer-related signaling pathways [ 59 ]. Small molecules containing zinc-binding groups, such as hydroxamic acids, have been among the most effective inhibitors of HDACs [ 60 , 61 ]. The 3-hydroxypyridin-2-thiones have shown potent and selective inhibitory activity for HDAC6 and HDAC8 with IC 50 values in the nM range [ 36 , 37 ] and are structurally similar to 1d and 1e .…”

Post-Translational Modifications That Drive Prostate Cancer Progression

“…While this strategy in prostate cancer still awaits to be further exploited, the (de-)acetylation inhibitors are already used in clinical trials. HDAC inhibitors vorinostat, pracinostat, panobinostat, and romidepsin underwent phase II clinical trials for prostate cancers but results were not satisfying to recommend phase III trials as majority of patients exhibited either toxicity or disease progression [ 435 ]. The CBP/p300 bromodomain inhibitor CCS1477, the only CBP/p300 inhibitor currently in clinical trials, is under clinical evaluation for the treatment of prostate cancer [ 436 ].…”