ABSTRACT
Androgen deprivation therapy remains the backbone of prostate cancer treatment given its pivotal role in the pathogenesis of prostate cancer. The growing knowledge of androgen receptor-independent (i.e. AR-null) prostate cancer cells, however, might advance the treatment paradigm of prostate cancer. Here, we examined the results of two recent studies, published in Cancer Cell by Bluemn and Shukla et al., and their impact in the future management of castration-resistant prostate cancer.
Androgen deprivation therapy (ADT) represents the backbone of advanced prostate cancer treatment given the pivotal role of androgen receptor (AR) signaling in the pathogenesis. However, nearly all tumors that initially respond to castration levels of testosterone progress to a lethal state called metastatic castration-resistant prostate cancer (mCRPC). Majority of the mechanisms responsible for progression to CRPC described thus far relates to maintenance of AR signaling in the setting of castration (e.g., AR activating mutations, AR amplification, overexpression of glucocorticoid receptor).Citation1 Based on the assumption that AR signaling remains critical throughout disease course, patients with mCRPC are treated with ADT for life enduring related adverse effects. Recent discoveries advance the knowledge regarding growing incidence of AR-independent prostate cancer and create an opportunity to challenge the treatment paradigm of CRPC by targeting these pathways in different stages with or without ADT. It also raises the question of whether it is necessary to continue AR antagonism and ADT when the disease is driven by other mechanisms.Citation2,Citation3
Heterogeneity in AR expression is a well-known phenomenon and it can be regulated during ADT. A study of 30 autopsies of men with CRPC showed downregulation of AR expression with 41% of tumor samples displaying <10% of AR expression suggesting the importance of alternate AR bypass mechanisms in disease progression.Citation4 Similarly, results from a recent study by BluemnCitation3 and colleagues with consecutive tissue necropsies from mCRPC patients describes a phenotypic shift with increasing frequency of tumors without AR expression or neuroendocrine features (“double-negative” tumors) over the past 2 decades as more effective AR antagonism emerged (5% in the period 1998–2011 to 23% in 2012–2016). AR-null tumor frequency in CRPC patients increased from 11.7% to 36.6% without significant change in recurrent genomic aberrations such as TP53 mutation and PTEN loss. In addition to detailed genomic characterization, the study showed that autocrine FGF signaling is activated in the absence of AR to maintain cell survival and growth via MAPK suggesting the therapeutic potential of blocking FGFR/MAPK pathways in AR-null tumors. Activity of these pathways was inversely associated with AR activity. Authors highlighted that since no recurrent genomic events involving FGFs/FGFRs were found, other processes, which can influence FGF transcription such as epigenetic regulation might explain possible mechanism.
Another important contribution to the understanding of AR-independent pathways in the setting of CRPC was recently provided by Shukla and colleagues describing that 30% of CRPC aberrantly express a gastrointestinal-lineage (PCa-GI) transcriptome regulated by Hepatocyte Nuclear Factor 4 Gamma (HNF4G).Citation2 The study showed that SPINK1 overexpression, previously shown to be associated with more rapid progression to castration resistance, is part of the PCa-GI transcriptome, and intensity of HNF4G and percentage of positive cases increase as primary prostate cancer progresses to CRPC. In fact, exogenous expression of HNF4G accelerated the progression to androgen-independent growth in vitro and enzalutamide resistance in vivo. Furthermore, enzalutamide selection pressure in vivo was found to increase HNF4G expression supporting its importance to AR-targeted therapy resistance by providing CRPC cells an alternative pathway for survival and growth.
Precision medicine-driven efforts targeting androgen-independent pathways in mCRPC have explored immunotherapies, prostate specific membrane antigen-targeting radiotherapies and pathways such as PARP, PI3K–Akt–mTOR, MAPK-ERK, TMPRSS2/ERG, Hippo, wnt, Hh and Notch.Citation5 Although some clinical studies such as one evaluating the checkpoint inhibitor pembrolizumab have shown promising preliminary results, the vast majority has been negative due to various reasons such as unselected populations, lack of efficacy of monotherapies, advanced stage cancer previously treated with multiple line regimens.Citation5 These treatment modalities frequently have their first evaluation in mCRPC setting with continuation of ADT with clones carrying molecular complexity that have evolved during multiple lines of therapy.
Molecular characterization and selection for AR-null tumors might allow evaluation of novel treatments at later stages when AR-null predominates and consider even discontinuation of ADT. In addition, evaluation of novel treatments in AR-null tumors at initial diagnosis of metastatic disease without ADT could be also considered if lack of contribution of AR signaling could be somehow documented. Real-time knowledge of contribution of AR signaling to pathogenesis and relative functional influence to tumor growth could determine if treatment efforts should be directed to other pathways or combinatorial strategies. To achieve these goals, genomic analysis of circulating tumor DNA (ctDNA) with its strong correlation with matched metastatic tissue specimen analysis provide an useful platform to direct therapies in real time in alignment with transcriptome analysis of AR regulated genes.Citation6 Similar molecular tool(s) for longitudinal monitoring of clonal evolution, pathway analyses and AR expression would be essential to accelerate the development of personalized therapy in prostate cancer and potentially relief patients from lifelong ADT adverse events when AR signaling no longer plays a pivotal role.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
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