Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Abstract

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

Identification of molecular subtypes and a prognostic signature based on m6A/m5C/m1A-related genes in lung adenocarcinoma

“…Patients in the high-risk group were sensitive to BIBW2992, bicalutamide, doxorubicin, embelin, gemcitabine, midostaurin, parthenolide, pazopanib, rapamycin, salubrinal, sunitinib, and tipifarnib, which can be used to treat a wide range of tumors. Bicalutamide, a second-generation oral nonsteroidal antiandrogen, is widely used to treat prostate cancer and triple-negative breast cancer 43 , 44 . Sunitinib is a tyrosine kinase inhibitor with antiangiogenic properties that plays a crucial role in the treatment of metastatic renal cell carcinoma 45 .…”

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“…Morgentaler suggested that the solution to this paradox lies in the concept of saturation, “in which maximal stimulation of prostate cancer growth is achieved at some relatively low concentration of testosterone.” 28 Fowler and Whitmore first proposed this model in 1981 29 . Further research aims to elucidate castrate‐resistant prostate cancer, androgen receptor mutations 30 and targeting of androgen signaling 31 …”

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“…enzalutamide, apalutamide, and darolutamide) as well as taxane-based chemotherapy (e.g. docetaxel and cabazitaxel) [ 5 , 6 ]. Options following standard treatments are often limited in their effectiveness [ 3 , 7 ].…”