Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

Abstract

In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens.Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option.Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.

Small-Molecule PROTACs for Cancer Immunotherapy

“…The bromodomain and extra-terminal domain (BET) protein family plays a vital role in epigenetic and transcriptional regulation [ 104 , 105 , 106 ]. Its immuno-regulating function is mainly associated with PD-L1 expression, which is mediated by bromodomain-containing protein 4 (BRD4) [ 104 , 105 , 107 ].…”

Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview

“…While it is recognizable that humans should not be involved in research on PCa, or as a matter a fact for any disease, until the safety and efficacy of the compounds have been established with reasonable confidence, the pharmacokinetics, DDI, and other drug deposition-related studies face lesser regulatory stringency than during drug development stage. Identification of resistant treatment regimen is primarily derivative of post-approval clinical studies where lower treatment efficacy provide the impetus for research at the preclinical level to develop drug-resistant cell lines and research design [ 113 , 114 ].…”

Clinical efficacy of different androgen deprivation therapies for prostate cancer and evaluation based on dynamic-contrast enhanced magnetic resonance imaging

“…Prostate cancer (PCa) mainly refers to the pathological changes in the tissues around the prostate gland affected by various complex factors, resulting in the growth dysfunction or irregular growth of acinar cells and eventually inducing malignant tumors ( Mori et al, 2022 ). Androgen deprivation therapy (ADT) is the main method to treat PCa, which can block androgens from testis and adrenal gland and has become the gold standard in the treatment of advanced PCa.…”