Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches

Abstract

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. While a majority of patients initially respond to ADT, most will eventually develop castrate-resistance, defined as disease progression despite serum testosterone levels of less than 20ng/dL. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. While these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate-resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.

Retracted: Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR‐145‐5p‐mediated regulation of AKAP12

“…Androgen deprivation therapy (ADT) first proposed by Charles Huggins et al on their seminal observations is highly effective in controlling metastatic prostate cancer 5. Although ADT is effective for some patients, most patients may develop castration resistance PCa (CRPC) 6. Docetaxel (DTX) has been subsequently used as a standard treatment for these patients with castration‐resistant prostate cancer (CRPC) 7.…”

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

“…Androgen receptor (AR) signalling is crucial for prostate tumour growth [9][10][11][12][13] . When bound to androgens, ARs translocate to the nucleus and transactivate target genes by interacting with other transcription factors such as forkhead-box A1 (FOXA1) 10 .…”

“…When bound to androgens, ARs translocate to the nucleus and transactivate target genes by interacting with other transcription factors such as forkhead-box A1 (FOXA1) 10 . Although the molecular mechanisms underlying prostate cancer progression to lethal hormone refractory prostate cancer (HRPC) [9][10][11][12][13] are incompletely understood, activation of downstream signals by hypersensitive or overexpressed ARs is considered to be important. The epigenetic status of prostate cancer cells is modulated by AR binding and the subsequent recruitment of co-activators or co-repressors [14][15][16][17][18] .…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…These events are often followed by alterations in the PI3K signaling, RB signaling and RAS/Raf signaling, which render the tumor more aggressive [176]. Finally, androgen-resistance occurs, which is consistent with the fact that most metastatic tumors have an alteration in the androgen signaling pathway [173,176,180]. While there was much effort in mechanistically unraveling these signaling pathways and their interplay, there is less knowledge about their specific impact on prostate cancer metabolism.…”

“…In the past decades several drivers for prostate cancer and progression were identified at the genomic, transcriptional and protein-level [119,[173][174][175][176][177][178][179][180][181][182]. The acquisition of these driver mutations and subsequent tumor progression could either follow a linear pathway or a molecular diversity model as suggested by Rubin et al, 2011 [178].…”