Molecular Mechanisms of Prostate Cancer Development: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Shigekatsu Maekawa.

Prostate cancer (PCa) is characterized by various genomic alterations that play a pivotal role in carcinogenesis. Efforts in precision medicine aimed at improving diagnosis, prevention, and surveillance based on genetic alterations are advancing. Notably, no tumor markers surpass prostate-specific antigen in specificity, and existing treatments primarily target the androgen receptor axis, with exceptions for patients with alterations in homologous recombination repair-related genes, such as BRCA1/2 and ATM, who may benefit from poly (ADP-ribose) polymerase inhibitors.

  • prostate cancer
  • next-generation sequencing
  • mutagenesis
  • signal pathways
  • cancer immunology

1. Introduction

Prostate cancer (PCa) ranks as the fourth most commonly diagnosed cancer globally, accounting for 7.3% of all cases. In 2020, PCa held the position of the second most prevalent cancer (at 14.1%) and the fifth leading cause of cancer-related mortality (at 6.8%) among men [1]. Factors such as advanced age, African descent, and a family history of the disease are associated with poorer prognoses for PCa [2].
Treatment for PCa primarily involves androgen deprivation therapy (ADT), androgen receptor (AR)-signaling inhibitors (ARSIs), and chemotherapy. Following initial hormone therapy, metastatic castration-sensitive PCa (mCSPC) often progresses to metastatic castration-resistant PCa (mCRPC) within approximately 1–2 years. The median survival time and cancer-specific mortality for mCRPC are 22 months (95% confidence interval [CI]: 21.0–22.9) and 30 months (95% CI: 28.3–31.7), respectively [4][3]. In one study, the 1- and 5-year survival rates for mCRPC were estimated at 58, 37, and 58% and 17, 4, and 9% in German, Swedish, and US cohorts, respectively [5][4]. In another study, the median overall survival (OS) for chemotherapy-naïve mCRPC was significantly longer in the ARSI group (treated with abiraterone acetate or enzalutamide; 34.7 and 35.3 months, respectively) than in the placebo group [6,7][5][6].
Recently, precision medicine targeting driver genes, such as treatment employing poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA mutations identified through companion diagnostics, has been realized. Next-generation sequencing (NGS) technology has facilitated comprehensive and exhaustive genome analysis, revealing a multitude of genetic mutations associated with cancer initiation and progression. Furthermore, NGS has enabled routine clinical examination of individual genetic abnormalities. Consequently, personalized treatments based on genetic anomalies have been developed, even in the context of PCa, with accumulating evidence supporting this approach. Recent reports have highlighted the utility of Decipher Prostate testing in determining the treatment approach for recurrence after radical prostatectomy [9][7]. Despite extensive genome-wide sequencing studies on PCa, no biomarker has surpassed PSA for several decades.

2. Genomic Alterations

In PCa, the involvement of driver genes is highly diverse in terms of both carcinogenesis and disease progression. This diversity varies significantly among different cases as well as across various stages of PCa. Considering the variation in driver genes, precision medicine assumes profound significance in the context of PCa. The most prevalent genetic anomalies observed in PCa include point mutations in genes such as SPOP, FOXA1, and TP53, as well as copy number alterations (CNAs) in AR, MYC, RB1, PTEN, CHD1, and fusion genes associated with the ETS (E26 transformation-specific) family [10,11,12,13,14,15,16,17][8][9][10][11][12][13][14][15]. Alterations in pathways involving AR, TP53, the cell cycle, and MYC are strongly associated with the development of castration resistance and OS. By contrast, alterations in the Wnt pathway and SPOP mutations are indicative of a more favorable prognosis [18,19,20,21,22,23][16][17][18][19][20][21]. Notably, changes in AR and PI3K/Akt pathway components appear to result from continuous systemic therapy [24,25][22][23]. The prevalence of specific alterations varies in different clinical contexts. For instance, alterations in TP53 (35% vs. 29%), BRCA2 (10% vs. 4%), PIK3CA (8% vs. 2%), RB1 (7% vs. 3%), and APC (11% vs. 9%) are more frequent in high-volume diseases than in low-volume diseases. Alterations in CDK12, PTEN, and FOXA1 are similarly detected between CSPC and CRPC, whereas those in ATM and RB1 exhibit a similar prevalence between de novo and recurrent metastatic disease, with CDK12 (6% vs. 1%) and FOXA1 (17% vs. 10%) alterations more commonly observed in the de novo metastatic state. The PI3K/Akt pathway is affected in 35–40% of mCSPC cases [18,19,20,21,22,23,28,31,32,33,34][16][17][18][19][20][21][24][25][26][27][28].  In mCRPC, the most frequently aberrant genes include AR (62.7%), the ETS family (56.7%), TP53 (53.3%), and PTEN (40.7%). The frequency of alterations in these genes is significantly higher than that observed in localized cancer [36][29]. In mCRPC, non-AR-related clinically actionable alterations include aberrations in the PI3K/Akt pathway (49%), DNA repair pathway (19%), RAF kinases (3%), CDK inhibitors (7%), and Wnt pathway (5%) [36][29]. Notably, alterations in AR, TP53, RB1, PTEN, and ATM are enriched in mCRPC when compared with those in mCSPC [28][24].

2.1. Fusion Genes from the ETS Family

Among the most prevalent genomic alterations in PCa are fusions involving androgen-regulated promoters with ERG and other members of the ETS family of transcription factors. ETS fusions are observed in over 50% of cases [10,36,38,39][8][29][30][31]. In particular, the TMPRSS2–ERG fusion represents the most frequent molecular alteration in PCa [40][32], occurring in 40–50% cases, equivalent to >100,000 cases annually in the United States alone [41][33]. Notably, Asian patients with PCa exhibit fewer TMPRSS2–ERG fusions than do Caucasian or African-American patients [42,43,44][34][35][36]. TMPRSS2 expression is upregulated by androgenic hormones in PCa cells but downregulated in androgen-independent PCa tissue [44][36]. Genetic polymorphisms associated with PCa susceptibility may vary by race and ethnicity.

2.2. AR and AR-Related Genes

The dysregulation of AR and AR pathway-related genes plays a central role in PCa pathogenesis. Abnormalities in the AR pathway include gene amplifications, mutations, splicing variants, and ligand-independent AR activity. Furthermore, these abnormalities can result from coding regions as well as AR enhancer region amplifications and genomic structural rearrangements capable of producing constitutively active truncated AR isoforms, notably AR splice variant 7 (AR-V7) [50][37]. Over 70% of PCa cases exhibit AR pathway aberrations, including those involving SPOP or FOXA1, with the majority resulting from direct alterations affecting AR through amplifications and mutations [36][29]. Alterations in androgen receptor signaling are more frequently observed in metastatic samples, with AR amplification or mutation being the most common alteration (50–80%). SPOP mutations, while present, are relatively less frequent in metastatic samples [10,36,51,52][8][29][38][39]. AR alterations are rarely observed prior to ADT, although they are enriched in patients with mCRPC who have a higher disease burden and prior exposure to ARSIs [53][40]. By contrast, changes in AR copy number status are not evident in patients treated with docetaxel or cabazitaxel [54,55][41][42]. SPOP plays a role in protein degradation by acting as a substrate adaptor, enabling ubiquitination by the Cullin3–RING complex [62][43]. In PCa, SPOP functions as a tumor-suppressor gene by promoting the degradation of multiple oncogenic substrates, including AR and ERG [63,64][44][45]. SPOP mutations represent the most common point mutations in localized PCa [10,12][8][10]. The frequency of SPOP mutations in localized disease (10–15%) and metastatic PCa (5–10%) aligns with the observation of a more favorable disease prognosis in de novo mCSPC [23][21]. Alterations in SPOP are enriched in locoregional and early-stage disease; therefore, tumors with SPOP mutations may exhibit increased sensitivity to ADT [12,26,28][10][24][46].

2.3. TP53

When comparing clonal alterations between a matched primary localized tumor and a subsequent metastatic tumor from the same patient, tumors acquired at a later stage typically exhibit a higher mutation count than do tumors acquired at an earlier stage. TP53 alterations emerge early in affected patients and are present in all tumors from the same patient. TP53 mutations are clonal, even in cases of both primary localized and subsequent metastatic PCa [28][24]. A high frequency of TP53 alterations is observed in primary localized tumors, consistent with prior reports of aggressive behavior of PCa caused by TP53 alterations [66,67,68][47][48][49]. The timing of TP53 alterations in tumors, specifically whether these alterations are present in tumors early in their evolution or acquired later during disease progression, remains uncertain. Somatic alterations in BRCA2 have been identified in matched tumors, suggesting that somatic loss-of-function alterations in this gene occur early in tumorigenesis. By contrast, alterations in AR do not occur early in matched samples, which is consistent with treatment-related changes that promote castration resistance [28][24].

2.4. Mitogen-Activated Protein Kinase (MAPK) Pathway

Genes within the MAPK pathway are affected in 25% of tumors [10][8]. The presence of RAF kinase fusions in 3% of individuals with mCRPC suggests the potential utility of pan-RAF inhibitors or MEK inhibitors [36][29].

2.5. PI3K/Akt Pathway

Alterations in the PI3K/Akt pathway constitute the second most frequently observed pathway aberration in metastatic PCa [10,36,69,70][8][29][50][51]. The PI3K/Akt pathway may be antagonized by several phosphatases, including PTEN and PHLPP. PI3K activation results in the phosphorylation of AKT and its downstream genes, including the mammalian target of rapamycin (mTOR). Phosphorylated AKT is an indicator of PI3K/Akt pathway activation [71[52][53],72], and AKT activates nuclear factor-κB (NF-κB) signaling in CRPC, with levels of NF-κB being higher in castration-resistant cell lines than in androgen-dependent cell lines [73][54]. PTEN, which leads to the downstream activation of the PI3K/Akt and AR signaling pathways, plays a crucial role in tumor suppression, and its loss is associated with poorer clinical outcomes in patients with mCRPC [18,53,74,75][16][40][55][56]. Considering that PTEN-deleted tumors may rely on PIK3CB owing to feedback inhibition from PIK3CA, the simultaneous loss and mutation of PTEN and PIK3CB could result in increased PI3K/Akt pathway activity. This observation suggests the existence of a subset of tumors for which a combination of PI3K and androgen signaling inhibition might be effective. In the context of the PI3K/Akt pathway, specific inhibitors targeting PIK3CB may be beneficial for individuals with mutations, amplifications, and/or fusions involving the related gene.

2.6. NF-κB Signaling

The NF-κB/Rel proteins include NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, RelB, and others. These proteins function as dimeric transcription factors, primarily regulating the transcription of genes involved in a wide range of biological processes such as apoptosis, angiogenesis, inflammation response, cell survival, inflammation, stress response, B-cell development, and lymphoid tissue formation [79,80,81,82,83,84][57][58][59][60][61][62]. The activation of NF-κB (p65) and Sonic Hedgehog pathways in PCa is positively correlated, and the overexpression of NF-κB(p65), SHh, and GLI1 is observed in aggressive PCa tissue cores featuring a high Gleason score and advanced clinical stage. These pathways play key roles in the progression of advanced PCa and are potential targets for therapeutic intervention [85][63]. The involvement of NF-κB signaling in the onset and maintenance of CRPC is considerable, irrespective of whether it is due to abnormal AR activity or AR-independent mechanisms [86][64]. Moreover, NF-κB plays a crucial role in the development of treatment resistance and metastasis in PCa. Specifically, the RelB-activated noncanonical NF-κB pathway could prolong and enhance NF-κB activity [87][65].

2.7. Cell Cycle Pathway

RB1 loss is detected in 21% of PCa cases [36][29]. Focal amplifications involving CCND1 (9%), as well as less frequent (<5%) events affecting CDKN2A/B, CDKN1B, and CDK4, are observed in mCRPC [36][29]. Disruptions in the cell cycle, such as CCND1 amplification or CDKN2A/B loss, may lead to an increased responsiveness to CDK4 inhibitors, as observed in other tumor types [27][66]. Pre-clinical findings indicate that selectively targeting CDK4/6 represents a therapeutic approach for both early-stage and advanced prostate PCa [92][67]. Mutations or deletions of TP53 and RB1 are more prevalent in metastatic than in localized PCa [10[8][29],36], and these alterations are associated with a poorer clinical outcome and aggressive behavior [35,66,67,93,94][47][48][68][69][70].

2.8. DNA Repair Pathway

Alterations in the DNA repair pathway are more frequent in mCRPC than in localized PCa or CSPC [10,36][8][29]. Genetic abnormalities associated with the DNA damage response (DDR) are observed in approximately 23–28% of mCRPC cases, including both germline and somatic variants [10,11,20,28,29,30][8][9][18][24][71][72].

2.8.1. HRR Genes

Among common gene abnormalities, BRCA2 and ATM mutations constitute a significant majority [28][24]. In advanced PCa, BRCA2 (7–13%), BRCA1 (0–1%), ATM (5–7%), and CDK12 (4–6%) exhibit frequent mutations [36,51,52,95][29][38][39][73]. The prevalence of pathological variants in BRCA1/2 and ATM varies across different stages of PCa [10,36,76,96][8][29][74][75]. ATM alterations are associated with a poor prognosis; germline mutations are linked to higher tumor grades and lethal PCa [97,98,99][76][77][78]. CDK12 alterations are associated with aggressive clinical features and a poor prognosis in mCRPC [100][79]. In a study of PCa patients who underwent radical prostatectomy or localized radiation therapy, both metastasis-free survival and disease-specific survival were significantly shorter in patients with BRCA mutations than in non-carriers [101][80]. In localized PCa, BRCA2 germline mutations are associated with early-onset, high-grade tumors and a poor prognosis [101,102][80][81]. BRCA2 alterations are enriched in mCRPC relative to their frequency in mCSPC [35][68].

2.8.2. MMR Genes and Microsatellite Instability (MSI)

Tumors with MMR gene deficiencies or MSI often exhibit an augmented antitumor immune response characterized by an increased density of tumor-infiltrating lymphocytes (TILs) [114,115][82][83]. This phenomenon is attributed to elevated mutation rates and enhanced levels of neoantigens in MMR-deficient tumors. Such neoantigens arise through various mechanisms, including mutant peptides, frameshift mutations, and insertions or deletions (indels) in coding microsatellites [116,117][84][85]. These neoantigens are presented on the cell surface by MHC-I molecules, facilitating the T-cell-mediated elimination of tumor cells. Approximately 3–8% of PCa cases, with a germline mutation rate of approximately 1%, are linked to the deficiency of MMR genes, including MSH2, MSH6, PMS2, and MLH1. Such deficiency leads to hypermutation, MSI, and characteristic trinucleotide mutational signatures [28,36,118,119,120,121,122,123][24][29][86][87][88][89][90][91]. MMR genes play crucial roles in the recognition and repair of incorrect insertions, deletions, and base misincorporations during DNA replication or recombination [124][92].

3. Immune Environment

In the context of PCa, the immune environment and hormone therapy involve macrophages/antigen-presenting cells (APCs), CD8-positive cytotoxic T lymphocytes, CD4-positive helper T lymphocytes, and natural killer (NK) cells, all of which recognize and target cancer cells, contributing to antitumor immunity. Several studies have reported on the expression of these cells within prostate tissues; notably, fewer TILs have been identified in poorly differentiated PCa than in benign prostatic hyperplasia, suggesting a potential link between immune cell deficiency and cancer progression. The infiltration of these immune cells within the tumor microenvironment of PCa tissue has also been associated with prognosis; patients with PCa and a higher number of infiltrating TILs tend to have better outcomes than those with fewer infiltrating TILs [134,135,136][93][94][95]. The examination of CD68-positive tumor-infiltrating macrophages (TAMs) in radical prostatectomy specimens of patients with PCa revealed that cases with a higher number of infiltrating cells were associated with a significantly worse prognosis for PSA recurrence than those with fewer infiltrating cells [137][96].

4. Epigenetic Modifications

Epigenetic traits represent inheritable characteristics resulting from chromosomal alterations or DNA modifications without alteration of the DNA sequence [145][97]. Epigenetic modifications, including acetylation, methylation, ubiquitination, and phosphorylation, play pivotal roles in transcription, DNA repair, and replication [146][98]. Epigenetic regulation is a dynamic and reversible process involving the addition of epigenetic marks to histones or DNA, the recognition or recruitment of these marks, and the removal of these marks by epigenetic writers, readers, and erasers, respectively. PCa is associated with alterations in DNA methylation, histone modification, chromatin accessibility, and 3D chromatin structure. Such changes contribute to disease development and progression by influencing gene expression, promoting cellular plasticity, and facilitating CRPC emergence under treatment pressure. The dysregulation of chromatin and epigenetics confers the complete range of cancer hallmarks by altering transcriptional regulation, mediating all defined hallmarks of cancer, and promoting cancer cell plasticity [147][99].

4.1. DNA Methylation

The contribution of DNA methylation to PCa development was first reported in the early 1990s [161][100]. Approximately 22% of tumors in PCa are associated with hypermethylation [162][101]. DNA methylation is linked to gene silencing and occurs when a methyl group is added to the C5 position of the cytosine residues in CpG dinucleotides [163][102]. DNMT (DNA methyltransferase) enzymes catalyze the addition of 5-methyl cytosine to DNA, which can be removed by DNA demethylases from the ten-eleven translocation (TET) family [164][103]. In addition, approximately 60% of all gene promoters are associated with CpG islands [165][104]. Cytidine methylation of regulatory sequences near GSTP1, which encodes an enzyme responsible for safeguarding DNA against oxidants and carcinogens, has been associated with prostate tumorigenesis [171][105]. In PCa, GSTP1 is methylated in its promoter region, leading to the diminished expression of GSTP1 in tumor cells. Hypermethylation of the GSTP1 promoter occurs in approximately 75% of pre-invasive high-grade prostatic intraepithelial neoplasms and in over 90% of prostate tumors and persists through all stages of PCa progression [172][106].  Promoter hypermethylation can lead to the silencing of not only tumor-suppressor genes but also key receptors, such as AR and ESR1. Additionally, cell adhesion genes (such as CD44 or CDH1), cell cycle genes (such as CCND2, CDKN1B, or SFN), and apoptosis-related genes (such as ASC, BCL2, DAPK, or PTGS2) can be affected by this process [176][107]. Although global hypomethylation is common in primary tumors, it becomes more pronounced in metastatic PCa [177][108].  DNMT inhibitors such as azacytidine and decitabine have been developed to target aberrant DNA hypermethylation; furthermore, their efficacy against PCa has been clinically evaluated (NSC127716). In a phase 1/2 study of azacitidine in combination with docetaxel in mCRPC, a PSA response was observed in 52% (10/19) of patients, with no dose-limiting toxicity reported [178][109].

4.2. Histone Methylation

Histones undergo methylation when one, two, or three methyl groups are added from S-adenosylmethionine to the side chains of arginine, lysine, and histidine residues. Histone methylations, such as H3K4me1, H3K9me2, and H3K9me3, are reduced in PCa tissues when compared with their levels in normal prostate tissues [179][110]. The increased genomic distribution of H3K27me3 in metastatic PCa can primarily be attributed to the overexpression of EZH2 [154][111], a histone methyltransferase. EZH2 plays a pivotal role in promoting lineage plasticity and differentiation changes, which are closely associated with neuroendocrine PCa (NEPC) [181][112]. The polycomb group proteins EZH2 and embryonic ectoderm development (EED), another member of the PRC2 complex, are currently under investigation as therapeutic targets [182][113]. EED functions as a direct regulator of AR and its downstream genes, working in conjunction with EZH2 in the context of AR-positive PCa [183][114]. EZH2 represents a promising target, and several EZH2 inhibitors have been identified in early-stage clinical studies [184][115].

4.3. Histone Acetylation

Histone acetylation involves the addition of an acetyl group to the lysine residues of histones, leading to the opening and activation of chromatin. Typically, this process is associated with the activation of transcription, whereas histone deacetylation is often linked to gene silencing [193][116]. Super-enhancers, which are clusters of enhancers marked by high H3K27ac levels, play a crucial role as drivers of oncogenic processes in cancer cells [194,195][117][118]. The activation of histone acetyltransferases, such as p300 and CREB-binding protein (CBP), is strongly associated with an increase in H3K27ac modification frequency [196][119]. Histone deacetylases (HDACs) are enzymes responsible for removing histone acetylation; thus far, several types of HDACs have been identified in humans [200][120]. Notably, there are five classes of HDAC inhibitors, including hydroxamic acids, cyclic tetrapeptides, short-chain carboxylic acids, benzamides, and ketoderivatives [201][121]. HDAC overexpression has been observed in various malignancies, including PCa [202][122]. Notably, the expression of HDAC1 and HDAC2 is positively correlated with higher Gleason scores in PCa, whereas that of HDAC1/2/3 is positively associated with the proliferative marker Ki67 [203][123]. 

5. Non-Coding RNAs

5.1. Long Non-Coding RNAs (lncRNAs) and Micro-RNAs (miRNAs)

lncRNAs have been implicated in prostate carcinogenesis. They exert their influence through various mechanisms, including regulation of the AR expression pathway, epithelial–mesenchymal transition, miRNAs, and the PI3K/Akt/mTOR pathway; these processes are governed by PCa gene expression marker 1 (PCGEM1), PlncRNA-1, colon cancer-associated transcript 2 (CCAT2), C-terminal binding protein 1 antisense (CTBP1-AS), growth arrest-specific 5 (GAS5), long intergenic non-protein-coding RNA 1296 (LINC01296), LOC400891, and LOC440040, etc. [207,208,209,210,211,212,213,214,215,216][124][125][126][127][128][129][130][131][132][133]. LINC00624 is overexpressed in both PCa tissues and cells and is associated with malignant progression. Furthermore, the relationship between NF-κB and PCa is linked to the expression of LINC00624, as it forms a co-regulatory axis with TEX10, stimulating NF-κB activity. Therefore, LINC00624 is hypothesized to function as an oncogene in PCa progression [90][134]. The activation of AKT and NF-κB signaling involves a crucial regulatory protein complex comprising PHLPP, FKBP51, and IKKα. The lncRNA PCAT1 is implicated in the regulation of the PHLPP/FKBP51/IKKα complex, directly binding to FKBP51 and excluding PHLPP from the complex. This regulation by PCAT1 contributes to CRPC progression by activating AKT and NF-κB signals [91][135]. Upregulated AR expression is a hallmark of CRPC and may serve as a mechanism facilitating AR signaling in the presence or absence of low endogenous androgen levels. Specific lncRNAs, such as CTBP1-AS and HOTAIR, exhibit upregulation following ADT, signifying their negative regulation by androgens. This upregulation of lncRNAs results in increased AR expression. CTBP1-AS upregulation leads to the downregulation of CTBP1, which negatively modulates AR by inhibiting androgen-mediated demethylation. Interaction with miRNAs is another mechanism by which lncRNAs regulate AR activity. PlncRNA-1 likely protects AR from miRNA-mediated suppression [211][128] by acting as a sponge for certain AR-targeting miRNAs, including miR-34c and miR-297. PCGEM1 and HOTAIR are reportedly targeted by miR-34a [219][136] and miR-145 [210][127], respectively. In PCa, both miR-145-5p (the guide strand) and miR-145-3p (the passenger strand) are downregulated. The introduction of these microRNAs into PCa cells reportedly suppresses their proliferative, migratory, and invasive capabilities. The cancer-suppressive functionality of both guide and passenger strands of several microRNAs, including miR-30a, miR-139, miR-143, and miR-145, has been established through large-scale cohort analysis using The Cancer Genome Atlas [221][137]. The miRNA expression profile of PCa using needle biopsy samples from CSPC and normal prostate tissues revealed that miR-222 and miR-31 exhibit cancer-suppressive functions [222][138]. miR-130b exhibits significant downregulation among miRNAs in PCa tissues, and its expression is significantly reduced in PCa cell lines as well. The decreased expression of miR-130b significantly promotes the proliferation, invasion, and tubule formation of PCa cells, whereas its overexpression suppresses angiogenesis in PCa. miR-130b directly regulates TNF-α, inhibiting the NF-κB signaling pathway and its downstream gene, VEGFA. Furthermore, VEGFA, by reducing the expression of miR-130b, contributes to a feedback loop involving miR-130b/TNF-α/NF-κB/VEGFA that is associated with angiogenesis in PCa [89][139]. In PCa, reports of liquid biopsy using upregulated or downregulated microRNAs in the blood (serum, plasma, exosomes) and urine as indicators have been increasing [224][140] [225][141]. Several studies suggest the detection of cell-free microRNAs, such as miR-141, miR-375, miR-107, and miR-221, in the blood as useful biomarkers for PCa [226][142]. Combining miR-17-3p and miR-1185-2-3p for PCa diagnosis has exhibited >90% sensitivity and specificity, highlighting its promise in clinical applications and circumventing the need for unnecessary prostate biopsies [227][143].

5.2. Role of miRNAs in PCa Drug Resistance

Growing evidence suggests that miRNAs play a pivotal role in anti-AR drug resistance. For example, miR-23b and miR-27b sensitize CRPC cells to flutamide by targeting CCNG1 [228][144]. miR-221 and miR-222, upregulated in CRPC cells, maintain resistance in PCa [229][145], and miR-663 affects castration resistance by modulating the AR signal [230][146]. In mCRPC, patients with higher levels of miR-375 and miR-3687 in whole blood exhibit a shorter time to progression with enzalutamide treatment [231][147]. Additionally, miRNAs play a key role in taxane resistance. Several miRNAs, including miR-34b-3p, miR-199a, miR-200b-3p, and miR-375, have been implicated in paclitaxel resistance [235,236][148][149]. Docetaxel resistance is associated with miR-375 and miR-323 upregulation, whereas miR-195, miR-204, miR-143, and miR-200b can enhance docetaxel sensitivity in PCa [237,238,239,240][150][151][152][153]. 

6. Prostate-Specific Membrane Antigen (PSMA)

PSMA is a type II transmembrane protein expressed in most high-grade, metastatic, androgen-insensitive, clinically significant cases of PCa. More than 90% of PCa cases exhibit PSMA overexpression at levels reported to be 100–1000 times higher than those in normal prostate tissue [247,248,249,250,251][154][155][156][157][158]; however, PSMA is scarcely expressed in benign or hyperplastic prostate tissue [252][159]. The organs reported to exhibit high PSMA expression, apart from the prostate, are the kidney, bladder, salivary glands, ganglion, liver, spleen, duodenum, and colon [253,254,255][160][161][162]. PSMA is a favorable target for molecular imaging [256,257,258,259,260,261,262][163][164][165][166][167][168][169] and therapy [263,264,265,266,267][170][171][172][173][174] in PCa. The US Food and Drug Administration (US FDA) has approved three types of radionuclides for positron emission tomography (PET) imaging of PSMA, namely F-18 piflufolastat PSMA, Ga-68 PSMA-11, and F-18 flotufolastat PSMA, for patients with PCa. PSMA PET-computed tomography (PET/CT) or magnetic resonance imaging (PET/MRI) are recommended for detecting metastases and restaging PCa in cases of biochemical recurrence [268][175]. In the Advanced Prostate Cancer Consensus Conference (APCCC 2022), 77% of panelists reached a consensus to perform PSMA PET/CT on the majority of patients with clinically localized high-risk PCa. However, 92% of panelists voted not to recommend PSMA PET/CT or MRI for patients with clinically localized favorable intermediate-risk (NCCN definition) PCa [269][176]. Determining superiority between 68Ga and 18F-PSMA PET/CT is challenging because their accumulation in normal organs is similar and their diagnostic accuracy does not differ significantly [260,261,262,270][167][168][169][177]. Radiation therapy utilizing the labeling of PSMA ligands to target PSMA-positive cells and the surrounding microenvironment involves both alpha and beta radionuclides such as 225Ac-PSMA and 177Lu-PSMA, respectively [255,271,272,273][162][178][179][180]. 

7. Precision Medicine: Genome-Based Therapy

7.1. PARP Inhibitors (PARPis) for mCRPC with Alterations in HRR Genes

PARP recognizes single-strand DNA breaks and facilitates the transportation of base-excision repair proteins for genetic repair. Conversely, several proteins, including BRCA, play a pivotal role in HRR, particularly in the repair of double-strand DNA breaks. DNA repair can still occur in cases where a malfunction occurs in either PARP or BRCA. However, the administration of PARPis prevents DNA repair in cases where cancer cells exhibit BRCA abnormalities [96,275,276,277,278][75][181][182][183][184]. PARPis traps PARP-1 on damaged DNA, inhibiting auto-poly(ADP-ribosyl)ation and enhancing DNA affinity for the catalytic site, ultimately leading to cell death [96,279,280,281][75][185][186][187]. PARPis, which were approved by the US FDA in 2023 and are used for monotherapy or combination therapy with other drugs for mCRPC, belong to four types: olaparib, niraparib, rucaparib, and talazoparib. Veliparib is currently undergoing clinical trials [287,288][188][189]. Preclinical studies have indicated variations in the ability of PARPi to trap PARP enzymes across different tumor cells, including PCa cells, with talazoparib exhibiting the highest PARP-trapping capacity among the tested inhibitors, followed by niraparib, olaparib, and rucaparib [289][190]. 

7.2. Akt Inhibitor for mCRPC with PTEN Deficiency

PTEN typically exerts tumor-suppressor effects by inhibiting the PI3K/Akt/mTOR signaling pathway. However, PTEN deficiency is present in approximately 50% of patients with mCRPC. Upon PTEN protein deficiency, signal transduction through PI3K and Akt occurs via genomic or non-genomic pathways, leading to the dysregulation of the cell cycle and cell proliferation, the enhancement of metabolic pathways such as those for glycolysis and protein translation, and the promotion of vascular neogenesis and cell survival pathways. These processes ultimately culminate in tumor formation and growth [299][191]. Ipataseltib is a novel, cooperative, and selective ATP-competitive small-molecule inhibitor targeting all three isoforms of Akt [301][192]. A phase 3 trial (IPATentia150 trial: NCT03072238) evaluating the combination therapy of ipatasertib and apalutamide revealed that the median rPFS of mCRPC patients with PTEN deficiency was 18.5 months (95% CI: 16.3–2.1 months) in the ipatasertib + apalutamide group and 16.5 months (95% CI: 13.9–17.0 months) in the placebo + apalutamide group. This combination therapy significantly increased rPFS by 23% (HR: 0.77, 95% CI: 0.61–0.98, p = 0.0335) [302,303][193][194]. Akt inhibitors are considered potential novel agents representing the precision medicine era for mCRPC, and a phase 3 randomized CAPItello-280 trial (NCT05348577) is underway to evaluate the efficacy and safety of capivasertib and docetaxel administration as compared to that of placebo and docetaxel administration in the treatment of patients with mCRPC [304][195].

7.3. Immune Checkpoint Inhibitors (ICIs) for mCRPC

The programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is pivotal in regulating T-cell activity [306,307,308][196][197][198]. Several clinical studies have assessed the efficacy of ICIs, including anti-PD-L1 (nivolumab, atezolizumab, durvalumab, and avelumab), anti-PD1 (pembrolizumab and nivolumab), and anti-CTLA4 (ipilimumab) antibodies. Although preliminary studies have indicated limited anticancer activity of ICIs [309[199][200],310], patient selection based on deficiencies in MMR genes is considered crucial, as this patient cohort can potentially respond to ICIs. The FDA has approved the use of the anti-PD1 antibody pembrolizumab for treating cancers, including PCa with MMR mutations or MSI [311][201]. Strong correlations were reported between immunohistochemical PD-L1 expression and the efficacy of PD-1 blockade in various malignant tumor cohorts. However, within these cohorts, only two patients had CRPC [312][202]; their samples revealed negative PD-L1 expression, suggesting the lack of a significant association. High PD-1 expression was observed in infiltrating T lymphocytes, specifically in CD8-positive prostate tissues, suggesting that they may not effectively mount an immune response [313][203]. 

8. Conclusions

PCa is characterized by its androgen dependency, with treatment primarily based on androgen signal deprivation. However, the involvement of driver genes in both the initiation and progression of PCa is highly diverse among cases. Precision medicine, which involves understanding individual genetic alterations and proposing tailored treatment strategies, is considered crucial in the context of PCa. The development of treatments based on genetic mutations such as PARPis for HRR gene mutations, AKT inhibitors for patients with genetic mutations in the PI3K/Akt pathway, and ICI for mutations in MMR genes and cases of MSI-high or high-tumor-mutational-burden CSPC and CRPC is anticipated. Monitoring the treatment progress of patients with PCa using liquid biopsy methods such as miRNA in blood or urine is a promising field that could significantly impact routine PCa treatment.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Center, M.M.; Jemal, A.; Lortet-Tieulent, J.; Ward, E.; Ferlay, J.; Brawley, O.; Bray, F. International variation in prostate cancer incidence and mortality rates. Eur. Urol. 2012, 61, 1079–1092.
  3. Gandaglia, G.; Karakiewicz, P.I.; Briganti, A.; Passoni, N.M.; Schiffmann, J.; Trudeau, V.; Graefen, M.; Montorsi, F.; Sun, M. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. Eur. Urol. 2015, 68, 325–334.
  4. Vassilev, Z.P.; Gabarró, M.S.; Kaye, J.A.; Saltus, C.W.; Riedel, O.; Scholle, O.; Mehtälä, J.; Korhonen, P.; Garbe, E.; Zong, J. Incidence of second primary malignancies in metastatic castration-resistant prostate cancer: Results from observational studies in three countries. Future Oncol. 2020, 16, 1889–1901.
  5. Ryan, C.J.; Smith, M.R.; Fizazi, K.; Saad, F.; Mulders, P.F.; Sternberg, C.N.; Miller, K.; Logothetis, C.J.; Shore, N.D.; Small, E.J.; et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015, 16, 152–160.
  6. Beer, T.M.; Armstrong, A.J.; Rathkopf, D.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Evans, C.P.; Kim, C.S.; Kimura, G.; et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur. Urol. 2017, 71, 151–154.
  7. Feng, F.Y.; Huang, H.-C.; Spratt, D.E.; Zhao, S.; Sandler, H.M.; Simko, J.P.; Davicioni, E.; Nguyen, P.L.; Pollack, A.; Efstathiou, J.A.; et al. Validation of a 22-Gene Genomic Classifier in Patients with Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial. JAMA Oncol. 2021, 7, 544–552.
  8. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell 2015, 163, 1011–1025.
  9. Baca, S.C.; Prandi, D.; Lawrence, M.S.; Mosquera, J.M.; Romanel, A.; Drier, Y.; Park, K.; Kitabayashi, N.; MacDonald, T.Y.; Ghandi, M.; et al. Punctuated evolution of prostate cancer genomes. Cell 2013, 153, 666–677.
  10. Barbieri, C.E.; Baca, S.C.; Lawrence, M.S.; Demichelis, F.; Blattner, M.; Theurillat, J.P.; White, T.A.; Stojanov, P.; Van Allen, E.; Stransky, N.; et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 2012, 44, 685–689.
  11. Berger, M.F.; Lawrence, M.S.; Demichelis, F.; Drier, Y.; Cibulskis, K.; Sivachenko, A.Y.; Sboner, A.; Esgueva, R.; Pflueger, D.; Sougnez, C.; et al. The genomic complexity of primary human prostate cancer. Nature 2011, 470, 214–220.
  12. Cooper, C.S.; Eeles, R.; Wedge, D.C.; Van Loo, P.; Gundem, G.; Alexandrov, L.B.; Kremeyer, B.; Butler, A.; Lynch, A.G.; Camacho, N.; et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat. Genet. 2015, 47, 367–372.
  13. Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010, 18, 11–22.
  14. Wang, X.S.; Shankar, S.; Dhanasekaran, S.M.; Ateeq, B.; Sasaki, A.T.; Jing, X.; Robinson, D.; Cao, Q.; Prensner, J.R.; Yocum, A.K.; et al. Characterization of KRAS rearrangements in metastatic prostate cancer. Cancer Discov. 2011, 1, 35–43.
  15. Tomlins, S.A.; Laxman, B.; Dhanasekaran, S.M.; Helgeson, B.E.; Cao, X.; Morris, D.S.; Menon, A.; Jing, X.; Cao, Q.; Han, B.; et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 2007, 448, 595–599.
  16. Kohli, M.; Tan, W.; Zheng, T.; Wang, A.; Montesinos, C.; Wong, C.; Du, P.; Jia, S.; Yadav, S.; Horvath, L.G.; et al. Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer. eBioMedicine 2020, 54, 102728.
  17. Stopsack, K.H.; Nandakumar, S.; Wibmer, A.G.; Haywood, S.; Weg, E.S.; Barnett, E.S.; Kim, C.J.; Carbone, E.A.; Vasselman, S.E.; Nguyen, B.; et al. Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer. Clin. Cancer Res. 2020, 26, 3230–3238.
  18. Mateo, J.; Seed, G.; Bertan, C.; Rescigno, P.; Dolling, D.; Figueiredo, I.; Miranda, S.; Nava Rodrigues, D.; Gurel, B.; Clarke, M.; et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J. Clin. Investig. 2020, 130, 1743–1751.
  19. Hamid, A.A.; Gray, K.P.; Shaw, G.; MacConaill, L.E.; Evan, C.; Bernard, B.; Loda, M.; Corcoran, N.M.; Van Allen, E.M.; Choudhury, A.D.; et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur. Urol. 2019, 76, 89–97.
  20. Deek, M.P.; Van der Eecken, K.; Phillips, R.; Parikh, N.R.; Isaacsson Velho, P.; Lotan, T.L.; Kishan, A.U.; Maurer, T.; Boutros, P.C.; Hovens, C.; et al. The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited. Eur. Urol. 2021, 80, 632–640.
  21. Swami, U.; Isaacsson Velho, P.; Nussenzveig, R.; Chipman, J.; Sacristan Santos, V.; Erickson, S.; Dharmaraj, D.; Alva, A.S.; Vaishampayan, U.N.; Esther, J.; et al. Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer. Eur. Urol. 2020, 78, 652–656.
  22. Annala, M.; Taavitsainen, S.; Khalaf, D.J.; Vandekerkhove, G.; Beja, K.; Sipola, J.; Warner, E.W.; Herberts, C.; Wong, A.; Fu, S.; et al. Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition. Clin. Cancer Res. 2021, 27, 4610–4623.
  23. Gundem, G.; Van Loo, P.; Kremeyer, B.; Alexandrov, L.B.; Tubio, J.M.C.; Papaemmanuil, E.; Brewer, D.S.; Kallio, H.M.L.; Högnäs, G.; Annala, M.; et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015, 520, 353–357.
  24. Abida, W.; Armenia, J.; Gopalan, A.; Brennan, R.; Walsh, M.; Barron, D.; Danila, D.; Rathkopf, D.; Morris, M.; Slovin, S.; et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis. Oncol. 2017, 2017, 1–16.
  25. Gilson, C.; Ingleby, F.; Gilbert, D.C.; Parry, M.A.; Atako, N.B.; Ali, A.; Hoyle, A.; Clarke, N.W.; Gannon, M.; Wanstall, C.; et al. Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results from a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial. JCO Precis. Oncol. 2020, 4, 882–897.
  26. Vandekerkhove, G.; Struss, W.J.; Annala, M.; Kallio, H.M.L.; Khalaf, D.; Warner, E.W.; Herberts, C.; Ritch, E.; Beja, K.; Loktionova, Y.; et al. Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer. Eur. Urol. 2019, 75, 667–675.
  27. Shenderov, E.; Isaacsson Velho, P.; Awan, A.H.; Wang, H.; Mirkheshti, N.; Lotan, T.L.; Carducci, M.A.; Pardoll, D.M.; Eisenberger, M.A.; Antonarakis, E.S. Genomic and clinical characterization of pulmonary-only metastatic prostate cancer: A unique molecular subtype. Prostate 2019, 79, 1572–1579.
  28. Fan, L.; Fei, X.; Zhu, Y.; Pan, J.; Sha, J.; Chi, C.; Gong, Y.; Du, X.; Zhou, L.; Dong, B.; et al. Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing. J. Urol. 2021, 205, 461–469.
  29. Robinson, D.; Van Allen, E.M.; Wu, Y.M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.M.; Montgomery, B.; Taplin, M.E.; Pritchard, C.C.; Attard, G.; et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015, 161, 1215–1228.
  30. Sboner, A.; Habegger, L.; Pflueger, D.; Terry, S.; Chen, D.Z.; Rozowsky, J.S.; Tewari, A.K.; Kitabayashi, N.; Moss, B.J.; Chee, M.S.; et al. FusionSeq: A modular framework for finding gene fusions by analyzing paired-end RNA-sequencing data. Genome Biol. 2010, 11, R104.
  31. Wang, K.; Singh, D.; Zeng, Z.; Coleman, S.J.; Huang, Y.; Savich, G.L.; He, X.; Mieczkowski, P.; Grimm, S.A.; Perou, C.M.; et al. MapSplice: Accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res. 2010, 38, e178.
  32. Tomlins, S.A.; Rhodes, D.R.; Perner, S.; Dhanasekaran, S.M.; Mehra, R.; Sun, X.W.; Varambally, S.; Cao, X.; Tchinda, J.; Kuefer, R.; et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005, 310, 644–648.
  33. Tomlins, S.A.; Bjartell, A.; Chinnaiyan, A.M.; Jenster, G.; Nam, R.K.; Rubin, M.A.; Schalken, J.A. ETS gene fusions in prostate cancer: From discovery to daily clinical practice. Eur. Urol. 2009, 56, 275–286.
  34. Magi-Galluzzi, C.; Tsusuki, T.; Elson, P.; Simmerman, K.; LaFargue, C.; Esgueva, R.; Klein, E.; Rubin, M.A.; Zhou, M. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate 2011, 71, 489–497.
  35. Miyagi, Y.; Sasaki, T.; Fujinami, K.; Sano, J.; Senga, Y.; Miura, T.; Kameda, Y.; Sakuma, Y.; Nakamura, Y.; Harada, M.; et al. ETS family-associated gene fusions in Japanese prostate cancer: Analysis of 194 radical prostatectomy samples. Modern Pathol. 2010, 23, 1492–1498.
  36. Maekawa, S.; Suzuki, M.; Arai, T.; Suzuki, M.; Kato, M.; Morikawa, T.; Kasuya, Y.; Kume, H.; Kitamura, T.; Homma, Y. TMPRSS2 Met160Val polymorphism: Significant association with sporadic prostate cancer, but not with latent prostate cancer in Japanese men. Int. J. Urol. 2014, 21, 1234–1238.
  37. Takeda, D.Y.; Spisák, S.; Seo, J.H.; Bell, C.; O’Connor, E.; Korthauer, K.; Ribli, D.; Csabai, I.; Solymosi, N.; Szállási, Z.; et al. A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. Cell 2018, 174, 422–432.e13.
  38. Abida, W.; Cyrta, J.; Heller, G.; Prandi, D.; Armenia, J.; Coleman, I.; Cieslik, M.; Benelli, M.; Robinson, D.; Van Allen, E.M.; et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl. Acad. Sci. USA 2019, 116, 11428–11436.
  39. Armenia, J.; Wankowicz, S.A.M.; Liu, D.; Gao, J.; Kundra, R.; Reznik, E.; Chatila, W.K.; Chakravarty, D.; Han, G.C.; Coleman, I.; et al. The long tail of oncogenic drivers in prostate cancer. Nat. Genet. 2018, 50, 645–651.
  40. Annala, M.; Vandekerkhove, G.; Khalaf, D.; Taavitsainen, S.; Beja, K.; Warner, E.W.; Sunderland, K.; Kollmannsberger, C.; Eigl, B.J.; Finch, D.; et al. Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer. Cancer Discov. 2018, 8, 444–457.
  41. Conteduca, V.; Jayaram, A.; Romero-Laorden, N.; Wetterskog, D.; Salvi, S.; Gurioli, G.; Scarpi, E.; Castro, E.; Marin-Aguilera, M.; Lolli, C.; et al. Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer. Eur. Urol. 2019, 75, 368–373.
  42. Conteduca, V.; Castro, E.; Wetterskog, D.; Scarpi, E.; Jayaram, A.; Romero-Laorden, N.; Olmos, D.; Gurioli, G.; Lolli, C.; Sáez, M.I.; et al. Plasma AR status and cabazitaxel in heavily treated metastatic castration-resistant prostate cancer. Eur. J. Cancer 2019, 116, 158–168.
  43. Zhuang, M.; Calabrese, M.F.; Liu, J.; Waddell, M.B.; Nourse, A.; Hammel, M.; Miller, D.J.; Walden, H.; Duda, D.M.; Seyedin, S.N.; et al. Structures of SPOP-substrate complexes: Insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell 2009, 36, 39–50.
  44. Gan, W.; Dai, X.; Lunardi, A.; Li, Z.; Inuzuka, H.; Liu, P.; Varmeh, S.; Zhang, J.; Cheng, L.; Sun, Y.; et al. SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression. Mol. Cell 2015, 59, 917–930.
  45. An, J.; Wang, C.; Deng, Y.; Yu, L.; Huang, H. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep. 2014, 6, 657–669.
  46. Boysen, G.; Barbieri, C.E.; Prandi, D.; Blattner, M.; Chae, S.S.; Dahija, A.; Nataraj, S.; Huang, D.; Marotz, C.; Xu, L.; et al. SPOP mutation leads to genomic instability in prostate cancer. eLife 2015, 4, e09207.
  47. Zhou, Z.; Flesken-Nikitin, A.; Corney, D.C.; Wang, W.; Goodrich, D.W.; Roy-Burman, P.; Nikitin, A.Y. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 2006, 66, 7889–7898.
  48. Mu, P.; Zhang, Z.; Benelli, M.; Karthaus, W.R.; Hoover, E.; Chen, C.C.; Wongvipat, J.; Ku, S.Y.; Gao, D.; Cao, Z.; et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017, 355, 84–88.
  49. Aparicio, A.M.; Shen, L.; Tapia, E.L.; Lu, J.F.; Chen, H.C.; Zhang, J.; Wu, G.; Wang, X.; Troncoso, P.; Corn, P.; et al. Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers. Clin. Cancer Res. 2016, 22, 1520–1530.
  50. Pourmand, G.; Ziaee, A.A.; Abedi, A.R.; Mehrsai, A.; Alavi, H.A.; Ahmadi, A.; Saadati, H.R. Role of PTEN gene in progression of prostate cancer. Urol. J. 2007, 4, 95–100.
  51. Reid, A.H.; Attard, G.; Ambroisine, L.; Fisher, G.; Kovacs, G.; Brewer, D.; Clark, J.; Flohr, P.; Edwards, S.; Berney, D.M.; et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer 2010, 102, 678–684.
  52. Brognard, J.; Sierecki, E.; Gao, T.; Newton, A.C. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol. Cell 2007, 25, 917–931.
  53. Mulholland, D.J.; Tran, L.M.; Li, Y.; Cai, H.; Morim, A.; Wang, S.; Plaisier, S.; Garraway, I.P.; Huang, J.; Graeber, T.G.; et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 2011, 19, 792–804.
  54. Gasparian, A.V.; Yao, Y.J.; Kowalczyk, D.; Lyakh, L.A.; Karseladze, A.; Slaga, T.J.; Budunova, I.V. The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J. Cell Sci. 2002, 115, 141–151.
  55. Ferraldeschi, R.; Nava Rodrigues, D.; Riisnaes, R.; Miranda, S.; Figueiredo, I.; Rescigno, P.; Ravi, P.; Pezaro, C.; Omlin, A.; Lorente, D.; et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur. Urol. 2015, 67, 795–802.
  56. Carver, B.S.; Chapinski, C.; Wongvipat, J.; Hieronymus, H.; Chen, Y.; Chandarlapaty, S.; Arora, V.K.; Le, C.; Koutcher, J.; Scher, H.; et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011, 19, 575–586.
  57. Hayden, M.S.; Ghosh, S. Shared principles in NF-kappaB signaling. Cell 2008, 132, 344–362.
  58. Perkins, N.D. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 2006, 25, 6717–6730.
  59. Sun, S.C. The noncanonical NF-κB pathway. Immunol. Rev. 2012, 246, 125–140.
  60. Gilmore, T.D. The Rel/NF-kappaB signal transduction pathway: Introduction. Oncogene 1999, 18, 6842–6844.
  61. Li, Q.; Verma, I.M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2002, 2, 725–734.
  62. Gilmore, T.D. Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene 2006, 25, 6680–6684.
  63. Vecchiotti, D.; Verzella, D.; Di Vito Nolfi, M.; D’Andrea, D.; Flati, I.; Di Francesco, B.; Cornice, J.; Alesse, E.; Capece, D.; Zazzeroni, F. Elevated NF-κB/SHh/GLI1 Signature Denotes a Worse Prognosis and Represent a Novel Potential Therapeutic Target in Advanced Prostate Cancer. Cells 2022, 11, 2118.
  64. Thomas-Jardin, S.E.; Dahl, H.; Nawas, A.F.; Bautista, M.; Delk, N.A. NF-κB signaling promotes castration-resistant prostate cancer initiation and progression. Pharmacol. Ther. 2020, 211, 107538.
  65. Wang, X.; Fang, Y.; Sun, W.; Xu, Z.; Zhang, Y.; Wei, X.; Ding, X.; Xu, Y. Endocrinotherapy resistance of prostate and breast cancer: Importance of the NF-κB pathway (Review). Int. J. Oncol. 2020, 56, 1064–1074.
  66. Finn, R.S.; Crown, J.P.; Lang, I.; Boer, K.; Bondarenko, I.M.; Kulyk, S.O.; Ettl, J.; Patel, R.; Pinter, T.; Schmidt, M.; et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol. 2015, 16, 25–35.
  67. Comstock, C.E.; Augello, M.A.; Goodwin, J.F.; de Leeuw, R.; Schiewer, M.J.; Ostrander, W.F., Jr.; Burkhart, R.A.; McClendon, A.K.; McCue, P.A.; Trabulsi, E.J.; et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene 2013, 32, 5481–5491.
  68. Van der Eecken, K.; Vanwelkenhuyzen, J.; Deek, M.P.; Tran, P.T.; Warner, E.; Wyatt, A.W.; Kwan, E.M.; Verbeke, S.; Van Dorpe, J.; Fonteyne, V.; et al. Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review. Eur. Urol. Oncol. 2021, 4, 914–923.
  69. Chen, Z.; Trotman, L.C.; Shaffer, D.; Lin, H.K.; Dotan, Z.A.; Niki, M.; Koutcher, J.A.; Scher, H.I.; Ludwig, T.; Gerald, W.; et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005, 436, 725–730.
  70. Hong, M.K.; Macintyre, G.; Wedge, D.C.; Van Loo, P.; Patel, K.; Lunke, S.; Alexandrov, L.B.; Sloggett, C.; Cmero, M.; Marass, F.; et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 2015, 6, 6605.
  71. Davies, A.; Azad, A.A.; Kwan, E.M. Genomic Alterations to Guide Treatment Selection in Metastatic Prostate Cancer. Crit. Rev. Oncog. 2022, 27, 61–80.
  72. He, Y.; Xu, W.; Xiao, Y.T.; Huang, H.; Gu, D.; Ren, S. Targeting signaling pathways in prostate cancer: Mechanisms and clinical trials. Signal Transduct. Target. Ther. 2022, 7, 198.
  73. Wu, Y.M.; Cieślik, M.; Lonigro, R.J.; Vats, P.; Reimers, M.A.; Cao, X.; Ning, Y.; Wang, L.; Kunju, L.P.; de Sarkar, N.; et al. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 2018, 173, 1770–1782.e14.
  74. Grasso, C.S.; Wu, Y.M.; Robinson, D.R.; Cao, X.; Dhanasekaran, S.M.; Khan, A.P.; Quist, M.J.; Jing, X.; Lonigro, R.J.; Brenner, J.C.; et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012, 487, 239–243.
  75. Mateo, J.; Carreira, S.; Sandhu, S.; Miranda, S.; Mossop, H.; Perez-Lopez, R.; Nava Rodrigues, D.; Robinson, D.; Omlin, A.; Tunariu, N.; et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N. Engl. J. Med. 2015, 373, 1697–1708.
  76. Neeb, A.; Herranz, N.; Arce-Gallego, S.; Miranda, S.; Buroni, L.; Yuan, W.; Athie, A.; Casals, T.; Carmichael, J.; Rodrigues, D.N.; et al. Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors. Eur. Urol. 2021, 79, 200–211.
  77. Wu, Y.; Yu, H.; Li, S.; Wiley, K.; Zheng, S.L.; LaDuca, H.; Gielzak, M.; Na, R.; Sarver, B.A.J.; Helfand, B.T.; et al. Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. Eur. Urol. Oncol. 2020, 3, 224–230.
  78. Na, R.; Zheng, S.L.; Han, M.; Yu, H.; Jiang, D.; Shah, S.; Ewing, C.M.; Zhang, L.; Novakovic, K.; Petkewicz, J.; et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur. Urol. 2017, 71, 740–747.
  79. de Bono, J.S.; De Giorgi, U.; Rodrigues, D.N.; Massard, C.; Bracarda, S.; Font, A.; Arranz Arija, J.A.; Shih, K.C.; Radavoi, G.D.; Xu, N.; et al. Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss. Clin. Cancer Res. 2019, 25, 928–936.
  80. Castro, E.; Goh, C.; Leongamornlert, D.; Saunders, E.; Tymrakiewicz, M.; Dadaev, T.; Govindasami, K.; Guy, M.; Ellis, S.; Frost, D.; et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur. Urol. 2015, 68, 186–193.
  81. Kote-Jarai, Z.; Leongamornlert, D.; Saunders, E.; Tymrakiewicz, M.; Castro, E.; Mahmud, N.; Guy, M.; Edwards, S.; O’Brien, L.; Sawyer, E.; et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: Implications for genetic testing in prostate cancer patients. Br. J. Cancer 2011, 105, 1230–1234.
  82. Turajlic, S.; Litchfield, K.; Xu, H.; Rosenthal, R.; McGranahan, N.; Reading, J.L.; Wong, Y.N.S.; Rowan, A.; Kanu, N.; Al Bakir, M.; et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: A pan-cancer analysis. Lancet Oncol. 2017, 18, 1009–1021.
  83. Willis, J.A.; Reyes-Uribe, L.; Chang, K.; Lipkin, S.M.; Vilar, E. Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate. Clin. Cancer Res. 2020, 26, 11–17.
  84. Schumacher, T.N.; Scheper, W.; Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 2019, 37, 173–200.
  85. Maby, P.; Tougeron, D.; Hamieh, M.; Mlecnik, B.; Kora, H.; Bindea, G.; Angell, H.K.; Fredriksen, T.; Elie, N.; Fauquembergue, E.; et al. Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy. Cancer Res. 2015, 75, 3446–3455.
  86. Abida, W.; Cheng, M.L.; Armenia, J.; Middha, S.; Autio, K.A.; Vargas, H.A.; Rathkopf, D.; Morris, M.J.; Danila, D.C.; Slovin, S.F.; et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019, 5, 471–478.
  87. Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421.
  88. Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Campbell, P.J.; Stratton, M.R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 2013, 3, 246–259.
  89. Antonarakis, E.S.; Isaacsson Velho, P.; Fu, W.; Wang, H.; Agarwal, N.; Sacristan Santos, V.; Maughan, B.L.; Pili, R.; Adra, N.; Sternberg, C.N.; et al. CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors. JCO Precis. Oncol. 2020, 4, 370–381.
  90. Pritchard, C.C.; Morrissey, C.; Kumar, A.; Zhang, X.; Smith, C.; Coleman, I.; Salipante, S.J.; Milbank, J.; Yu, M.; Grady, W.M.; et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat. Commun. 2014, 5, 4988.
  91. Pritchard, C.C.; Mateo, J.; Walsh, M.F.; De Sarkar, N.; Abida, W.; Beltran, H.; Garofalo, A.; Gulati, R.; Carreira, S.; Eeles, R.; et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N. Engl. J. Med. 2016, 375, 443–453.
  92. Jiricny, J. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 2006, 7, 335–346.
  93. Ebelt, K.; Babaryka, G.; Figel, A.M.; Pohla, H.; Buchner, A.; Stief, C.G.; Eisenmenger, W.; Kirchner, T.; Schendel, D.J.; Noessner, E. Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma. Prostate 2008, 68, 1–10.
  94. Gannon, P.O.; Poisson, A.O.; Delvoye, N.; Lapointe, R.; Mes-Masson, A.M.; Saad, F. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J. Immunol. Methods 2009, 348, 9–17.
  95. Hussein, M.R.; Al-Assiri, M.; Musalam, A.O. Phenotypic characterization of the infiltrating immune cells in normal prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma. Exp. Mol. Pathol. 2009, 86, 108–113.
  96. Shirotake, S.; Miyajima, A.; Kosaka, T.; Tanaka, N.; Kikuchi, E.; Mikami, S.; Okada, Y.; Oya, M. Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer. Am. J. Pathol. 2012, 180, 1008–1016.
  97. Berger, S.L.; Kouzarides, T.; Shiekhattar, R.; Shilatifard, A. An operational definition of epigenetics. Genes Dev. 2009, 23, 781–783.
  98. Dawson, M.A.; Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 2012, 150, 12–27.
  99. Kukkonen, K.; Taavitsainen, S.; Huhtala, L.; Uusi-Makela, J.; Granberg, K.J.; Nykter, M.; Urbanucci, A. Chromatin and Epigenetic Dysregulation of Prostate Cancer Development, Progression, and Therapeutic Response. Cancers 2021, 13, 3325.
  100. Conteduca, V.; Hess, J.; Yamada, Y.; Ku, S.Y.; Beltran, H. Epigenetics in prostate cancer: Clinical implications. Transl. Androl. Urol. 2021, 10, 3104–3116.
  101. Zhao, S.G.; Chen, W.S.; Li, H.; Foye, A.; Zhang, M.; Sjöström, M.; Aggarwal, R.; Playdle, D.; Liao, A.; Alumkal, J.J.; et al. The DNA methylation landscape of advanced prostate cancer. Nat. Genet. 2020, 52, 778–789.
  102. Kulis, M.; Esteller, M. DNA methylation and cancer. Adv. Genet. 2010, 70, 27–56.
  103. Rasmussen, K.D.; Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016, 30, 733–750.
  104. Antequera, F. Structure, function and evolution of CpG island promoters. Cell. Mol. Life Sci. CMLS 2003, 60, 1647–1658.
  105. Stein, R.; Gruenbaum, Y.; Pollack, Y.; Razin, A.; Cedar, H. Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc. Natl. Acad. Sci. USA 1982, 79, 61–65.
  106. Bastian, P.J.; Yegnasubramanian, S.; Palapattu, G.S.; Rogers, C.G.; Lin, X.; De Marzo, A.M.; Nelson, W.G. Molecular biomarker in prostate cancer: The role of CpG island hypermethylation. Eur. Urol. 2004, 46, 698–708.
  107. Graça, I.; Pereira-Silva, E.; Henrique, R.; Packham, G.; Crabb, S.J.; Jerónimo, C. Epigenetic modulators as therapeutic targets in prostate cancer. Clin. Epigenet. 2016, 8, 98.
  108. Yegnasubramanian, S.; Haffner, M.C.; Zhang, Y.; Gurel, B.; Cornish, T.C.; Wu, Z.; Irizarry, R.A.; Morgan, J.; Hicks, J.; DeWeese, T.L.; et al. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res. 2008, 68, 8954–8967.
  109. Singal, R.; Ramachandran, K.; Gordian, E.; Quintero, C.; Zhao, W.; Reis, I.M. Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Clin. Genitourin. Cancer 2015, 13, 22–31.
  110. Ellinger, J.; Kahl, P.; von der Gathen, J.; Rogenhofer, S.; Heukamp, L.C.; Gütgemann, I.; Walter, B.; Hofstädter, F.; Büttner, R.; Müller, S.C.; et al. Global levels of histone modifications predict prostate cancer recurrence. Prostate 2010, 70, 61–69.
  111. Varambally, S.; Dhanasekaran, S.M.; Zhou, M.; Barrette, T.R.; Kumar-Sinha, C.; Sanda, M.G.; Ghosh, D.; Pienta, K.J.; Sewalt, R.G.; Otte, A.P.; et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002, 419, 624–629.
  112. Dardenne, E.; Beltran, H.; Benelli, M.; Gayvert, K.; Berger, A.; Puca, L.; Cyrta, J.; Sboner, A.; Noorzad, Z.; MacDonald, T.; et al. N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. Cancer Cell 2016, 30, 563–577.
  113. Italiano, A.; Soria, J.C.; Toulmonde, M.; Michot, J.M.; Lucchesi, C.; Varga, A.; Coindre, J.M.; Blakemore, S.J.; Clawson, A.; Suttle, B.; et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: A first-in-human, open-label, phase 1 study. Lancet Oncol. 2018, 19, 649–659.
  114. Liu, Q.; Wang, G.; Li, Q.; Jiang, W.; Kim, J.S.; Wang, R.; Zhu, S.; Wang, X.; Yan, L.; Yi, Y.; et al. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. Int. J. Cancer 2019, 145, 415–426.
  115. Aggarwal, R.R.; Schweizer, M.T.; Nanus, D.M.; Pantuck, A.J.; Heath, E.I.; Campeau, E.; Attwell, S.; Norek, K.; Snyder, M.; Bauman, L.; et al. A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer. Clin. Cancer Res. 2020, 26, 5338–5347.
  116. Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 1998, 12, 599–606.
  117. Lovén, J.; Hoke, H.A.; Lin, C.Y.; Lau, A.; Orlando, D.A.; Vakoc, C.R.; Bradner, J.E.; Lee, T.I.; Young, R.A. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 2013, 153, 320–334.
  118. Wen, S.; He, Y.; Wang, L.; Zhang, J.; Quan, C.; Niu, Y.; Huang, H. Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in prostate cancer. Oncogene 2020, 39, 6556–6571.
  119. Hnisz, D.; Abraham, B.J.; Lee, T.I.; Lau, A.; Saint-André, V.; Sigova, A.A.; Hoke, H.A.; Young, R.A. Super-enhancers in the control of cell identity and disease. Cell 2013, 155, 934–947.
  120. Seto, E.; Yoshida, M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 2014, 6, a018713.
  121. Roche, J.; Bertrand, P. Inside HDACs with more selective HDAC inhibitors. Eur. J. Med. Chem. 2016, 121, 451–483.
  122. Ropero, S.; Esteller, M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol. 2007, 1, 19–25.
  123. Weichert, W.; Röske, A.; Gekeler, V.; Beckers, T.; Stephan, C.; Jung, K.; Fritzsche, F.R.; Niesporek, S.; Denkert, C.; Dietel, M.; et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br. J. Cancer 2008, 98, 604–610.
  124. Takayama, K.; Horie-Inoue, K.; Katayama, S.; Suzuki, T.; Tsutsumi, S.; Ikeda, K.; Urano, T.; Fujimura, T.; Takagi, K.; Takahashi, S.; et al. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J. 2013, 32, 1665–1680.
  125. Zheng, J.; Zhao, S.; He, X.; Zheng, Z.; Bai, W.; Duan, Y.; Cheng, S.; Wang, J.; Liu, X.; Zhang, G. The up-regulation of long non-coding RNA CCAT2 indicates a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Biochem. Biophys. Res. Commun. 2016, 480, 508–514.
  126. Yang, L.; Lin, C.; Jin, C.; Yang, J.C.; Tanasa, B.; Li, W.; Merkurjev, D.; Ohgi, K.A.; Meng, D.; Zhang, J.; et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013, 500, 598–602.
  127. He, J.H.; Zhang, J.Z.; Han, Z.P.; Wang, L.; Lv, Y.B.; Li, Y.G. Reciprocal regulation of PCGEM1 and miR-145 promote proliferation of LNCaP prostate cancer cells. J. Exp. Clin. Cancer Res. CR 2014, 33, 72.
  128. Fang, Z.; Xu, C.; Li, Y.; Cai, X.; Ren, S.; Liu, H.; Wang, Y.; Wang, F.; Chen, R.; Qu, M.; et al. A feed-forward regulatory loop between androgen receptor and PlncRNA-1 promotes prostate cancer progression. Cancer Lett. 2016, 374, 62–74.
  129. Prensner, J.R.; Sahu, A.; Iyer, M.K.; Malik, R.; Chandler, B.; Asangani, I.A.; Poliakov, A.; Vergara, I.A.; Alshalalfa, M.; Jenkins, R.B.; et al. The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 2014, 5, 1434–1438.
  130. Hung, C.L.; Wang, L.Y.; Yu, Y.L.; Chen, H.W.; Srivastava, S.; Petrovics, G.; Kung, H.J. A long noncoding RNA connects c-Myc to tumor metabolism. Proc. Natl. Acad. Sci. USA 2014, 111, 18697–18702.
  131. Wu, J.; Cheng, G.; Zhang, C.; Zheng, Y.; Xu, H.; Yang, H.; Hua, L. Long noncoding RNA LINC01296 is associated with poor prognosis in prostate cancer and promotes cancer-cell proliferation and metastasis. OncoTargets Ther. 2017, 10, 1843–1852.
  132. Wang, J.; Cheng, G.; Li, X.; Pan, Y.; Qin, C.; Yang, H.; Hua, L.; Wang, Z. Overexpression of long non-coding RNA LOC400891 promotes tumor progression and poor prognosis in prostate cancer. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2016, 37, 9603–9613.
  133. Zhang, C.; Liu, C.; Wu, J.; Zheng, Y.; Xu, H.; Cheng, G.; Hua, L. Upregulation of long noncoding RNA LOC440040 promotes tumor progression and predicts poor prognosis in patients with prostate cancer. OncoTargets Ther. 2017, 10, 4945–4954.
  134. Zhou, J.; Li, J.; Qian, C.; Qiu, F.; Shen, Q.; Tong, R.; Yang, Q.; Xu, J.; Zheng, B.; Lv, J.; et al. LINC00624/TEX10/NF-κB axis promotes proliferation and migration of human prostate cancer cells. Biochem. Biophys. Res. Commun. 2022, 601, 1–8.
  135. Shang, Z.; Yu, J.; Sun, L.; Tian, J.; Zhu, S.; Zhang, B.; Dong, Q.; Jiang, N.; Flores-Morales, A.; Chang, C.; et al. LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex. Nucleic Acids Res. 2019, 47, 4211–4225.
  136. Chiyomaru, T.; Yamamura, S.; Fukuhara, S.; Yoshino, H.; Kinoshita, T.; Majid, S.; Saini, S.; Chang, I.; Tanaka, Y.; Enokida, H.; et al. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS ONE 2013, 8, e70372.
  137. Mitra, R.; Adams, C.M.; Jiang, W.; Greenawalt, E.; Eischen, C.M. Pan-cancer analysis reveals cooperativity of both strands of microRNA that regulate tumorigenesis and patient survival. Nat. Commun. 2020, 11, 968.
  138. Fuse, M.; Kojima, S.; Enokida, H.; Chiyomaru, T.; Yoshino, H.; Nohata, N.; Kinoshita, T.; Sakamoto, S.; Naya, Y.; Nakagawa, M.; et al. Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer. J. Hum. Genet. 2012, 57, 691–699.
  139. Mu, H.Q.; He, Y.H.; Wang, S.B.; Yang, S.; Wang, Y.J.; Nan, C.J.; Bao, Y.F.; Xie, Q.P.; Chen, Y.H. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis. Clin. Transl. Oncol. 2020, 22, 111–121.
  140. Mitchell, P.S.; Parkin, R.K.; Kroh, E.M.; Fritz, B.R.; Wyman, S.K.; Pogosova-Agadjanyan, E.L.; Peterson, A.; Noteboom, J.; O’Briant, K.C.; Allen, A.; et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518.
  141. Ponti, G.; Maccaferri, M.; Percesepe, A.; Tomasi, A.; Ozben, T. Liquid biopsy with cell free DNA: New horizons for prostate cancer. Crit. Rev. Clin. Lab. Sci. 2021, 58, 60–76.
  142. Endzeliņš, E.; Melne, V.; Kalniņa, Z.; Lietuvietis, V.; Riekstiņa, U.; Llorente, A.; Linē, A. Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: A systematic review. Mol. Cancer 2016, 15, 41.
  143. Urabe, F.; Matsuzaki, J.; Yamamoto, Y.; Kimura, T.; Hara, T.; Ichikawa, M.; Takizawa, S.; Aoki, Y.; Niida, S.; Sakamoto, H.; et al. Large-scale Circulating microRNA Profiling for the Liquid Biopsy of Prostate Cancer. Clin. Cancer Res. 2019, 25, 3016–3025.
  144. Pimenta, R.C.; Viana, N.I.; Amaral, G.Q.; Park, R.; Morais, D.R.; Pontes, J., Jr.; Guimaraes, V.R.; Camargo, J.A.; Leite, K.R.; Nahas, W.C.; et al. MicroRNA-23b and microRNA-27b plus flutamide treatment enhances apoptosis rate and decreases CCNG1 expression in a castration-resistant prostate cancer cell line. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2018, 40, 1010428318803011.
  145. Sun, T.; Wang, Q.; Balk, S.; Brown, M.; Lee, G.S.; Kantoff, P. The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res. 2009, 69, 3356–3363.
  146. Jiao, L.; Deng, Z.; Xu, C.; Yu, Y.; Li, Y.; Yang, C.; Chen, J.; Liu, Z.; Huang, G.; Li, L.C.; et al. miR-663 induces castration-resistant prostate cancer transformation and predicts clinical recurrence. J. Cell. Physiol. 2014, 229, 834–844.
  147. Benoist, G.E.; van Oort, I.M.; Boerrigter, E.; Verhaegh, G.W.; van Hooij, O.; Groen, L.; Smit, F.; de Mol, P.; Hamberg, P.; Dezentjé, V.O.; et al. Prognostic Value of Novel Liquid Biomarkers in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: A Prospective Observational Study. Clin. Chem. 2020, 66, 842–851.
  148. Samli, H.; Samli, M.; Vatansever, B.; Ardicli, S.; Aztopal, N.; Dincel, D.; Sahin, A.; Balci, F. Paclitaxel resistance and the role of miRNAs in prostate cancer cell lines. World J. Urol. 2019, 37, 1117–1126.
  149. Chen, L.; Cao, H.; Feng, Y. MiR-199a suppresses prostate cancer paclitaxel resistance by targeting YES1. World J. Urol. 2018, 36, 357–365.
  150. Ma, X.; Zou, L.; Li, X.; Chen, Z.; Lin, Q.; Wu, X. MicroRNA-195 regulates docetaxel resistance by targeting clusterin in prostate cancer. Biomed. Pharmacother. 2018, 99, 445–450.
  151. Wu, G.; Wang, J.; Chen, G.; Zhao, X. microRNA-204 modulates chemosensitivity and apoptosis of prostate cancer cells by targeting zinc-finger E-box-binding homeobox 1 (ZEB1). Am. J. Transl. Res. 2017, 9, 3599–3610.
  152. Xu, B.; Niu, X.; Zhang, X.; Tao, J.; Wu, D.; Wang, Z.; Li, P.; Zhang, W.; Wu, H.; Feng, N.; et al. miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS. Mol. Cell. Biochem. 2011, 350, 207–213.
  153. Yu, J.; Lu, Y.; Cui, D.; Li, E.; Zhu, Y.; Zhao, Y.; Zhao, F.; Xia, S. miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol. Rep. 2014, 31, 910–918.
  154. Lenzo, N.P.; Meyrick, D.; Turner, J.H. Review of Gallium-68 PSMA PET/CT Imaging in the Management of Prostate Cancer. Diagnostics 2018, 8, 16.
  155. Bostwick, D.G.; Pacelli, A.; Blute, M.; Roche, P.; Murphy, G.P. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: A study of 184 cases. Cancer 1998, 82, 2256–2261.
  156. Kusumi, T.; Koie, T.; Tanaka, M.; Matsumoto, K.; Sato, F.; Kusumi, A.; Ohyama, C.; Kijima, H. Immunohistochemical detection of carcinoma in radical prostatectomy specimens following hormone therapy. Pathol. Int. 2008, 58, 687–694.
  157. Mannweiler, S.; Amersdorfer, P.; Trajanoski, S.; Terrett, J.A.; King, D.; Mehes, G. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol. Oncol. Res. POR 2009, 15, 167–172.
  158. Ananias, H.J.; van den Heuvel, M.C.; Helfrich, W.; de Jong, I.J. Expression of the gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in lymph node and bone metastases of prostate cancer. Prostate 2009, 69, 1101–1108.
  159. Elsässer-Beile, U.; Bühler, P.; Wolf, P. Targeted therapies for prostate cancer against the prostate specific membrane antigen. Curr. Drug Targets 2009, 10, 118–125.
  160. Tasch, J.; Gong, M.; Sadelain, M.; Heston, W.D. A unique folate hydrolase, prostate-specific membrane antigen (PSMA): A target for immunotherapy? Crit. Rev. Immunol. 2001, 21, 249–261.
  161. Sokoloff, R.L.; Norton, K.C.; Gasior, C.L.; Marker, K.M.; Grauer, L.S. A dual-monoclonal sandwich assay for prostate-specific membrane antigen: Levels in tissues, seminal fluid and urine. Prostate 2000, 43, 150–157.
  162. Violet, J.; Jackson, P.; Ferdinandus, J.; Sandhu, S.; Akhurst, T.; Iravani, A.; Kong, G.; Kumar, A.R.; Thang, S.P.; Eu, P.; et al. Dosimetry of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes. J. Nucl. Med. 2019, 60, 517–523.
  163. Afshar-Oromieh, A.; Avtzi, E.; Giesel, F.L.; Holland-Letz, T.; Linhart, H.G.; Eder, M.; Eisenhut, M.; Boxler, S.; Hadaschik, B.A.; Kratochwil, C.; et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 2015, 42, 197–209.
  164. Maurer, T.; Gschwend, J.E.; Rauscher, I.; Souvatzoglou, M.; Haller, B.; Weirich, G.; Wester, H.J.; Heck, M.; Kübler, H.; Beer, A.J.; et al. Diagnostic Efficacy of 68Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J. Urol. 2016, 195, 1436–1443.
  165. Budäus, L.; Leyh-Bannurah, S.R.; Salomon, G.; Michl, U.; Heinzer, H.; Huland, H.; Graefen, M.; Steuber, T.; Rosenbaum, C. Initial Experience of 68Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur. Urol. 2016, 69, 393–396.
  166. Afshar-Oromieh, A.; Malcher, A.; Eder, M.; Eisenhut, M.; Linhart, H.G.; Hadaschik, B.A.; Holland-Letz, T.; Giesel, F.L.; Kratochwil, C.; Haufe, S.; et al. PET imaging with a gallium-labelled PSMA ligand for the diagnosis of prostate cancer: Biodistribution in humans and first evaluation of tumour lesions. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 486–495.
  167. Ferreira, G.; Iravani, A.; Hofman, M.S.; Hicks, R.J. Intra-individual comparison of 68Ga-PSMA-11 and 18F-DCFPyL normal-organ biodistribution. Cancer Imaging 2019, 19, 23.
  168. Kroenke, M.; Mirzoyan, L.; Horn, T.; Peeken, J.C.; Wurzer, A.; Wester, H.J.; Makowski, M.; Weber, W.A.; Eiber, M.; Rauscher, I. Matched-Pair Comparison of 68Ga-PSMA-11 and (18)F-rhPSMA-7 PET/CT in Patients with Primary and Biochemical Recurrence of Prostate Cancer: Frequency of Non-Tumor-Related Uptake and Tumor Positivity. J. Nucl. Med. 2021, 62, 1082–1088.
  169. Huang, S.; Ong, S.; McKenzie, D.; Mirabelli, A.; Chen, D.C.; Chengodu, T.; Murphy, D.G.; Hofman, M.S.; Lawrentschuk, N.; Perera, M. Comparison of 18F-based PSMA radiotracers with Ga-PSMA-11 in PET/CT imaging of prostate cancer-a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2023.
  170. Sartor, O.; de Bono, J.; Chi, K.N.; Fizazi, K.; Herrmann, K.; Rahbar, K.; Tagawa, S.T.; Nordquist, L.T.; Vaishampayan, N.; El-Haddad, G.; et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2021, 385, 1091–1103.
  171. Zechmann, C.M.; Afshar-Oromieh, A.; Armor, T.; Stubbs, J.B.; Mier, W.; Hadaschik, B.; Joyal, J.; Kopka, K.; Debus, J.; Babich, J.W.; et al. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur. J. Nucl. Med. Mol. Imaging 2014, 41, 1280–1292.
  172. Ahmadzadehfar, H.; Eppard, E.; Kürpig, S.; Fimmers, R.; Yordanova, A.; Schlenkhoff, C.D.; Gärtner, F.; Rogenhofer, S.; Essler, M. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget 2016, 7, 12477–12488.
  173. Heck, M.M.; Retz, M.; D’Alessandria, C.; Rauscher, I.; Scheidhauer, K.; Maurer, T.; Storz, E.; Janssen, F.; Schottelius, M.; Wester, H.J.; et al. Systemic Radioligand Therapy with 177Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer. J. Urol. 2016, 196, 382–391.
  174. Hofman, M.S.; Emmett, L.; Sandhu, S.; Iravani, A.; Buteau, J.P.; Joshua, A.M.; Goh, J.C.; Pattison, D.A.; Tan, T.H.; Kirkwood, I.D.; et al. Overall survival with Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): Secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2023, 25, 99–107.
  175. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Prostate Cancer (Version 4.2023). Available online: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (accessed on 23 November 2023).
  176. Gillessen, S.; Bossi, A.; Davis, I.D.; de Bono, J.; Fizazi, K.; James, N.D.; Mottet, N.; Shore, N.; Small, E.; Smith, M.; et al. Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022. Eur. Urol. 2023, 83, 267–293.
  177. Evangelista, L.; Maurer, T.; van der Poel, H.; Alongi, F.; Kunikowska, J.; Laudicella, R.; Fanti, S.; Hofman, M.S. Ga-PSMA Versus PSMA Positron Emission Tomography/Computed Tomography in the Staging of Primary and Recurrent Prostate Cancer. A Systematic Review of the Literature. Eur. Urol. Oncol. 2022, 5, 273–282.
  178. Sathekge, M.M.; Bruchertseifer, F.; Vorster, M.; Morgenstern, A.; Lawal, I.O. Global experience with PSMA-based alpha therapy in prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 2021, 49, 30–46.
  179. Afshar-Oromieh, A.; Hetzheim, H.; Kratochwil, C.; Benesova, M.; Eder, M.; Neels, O.C.; Eisenhut, M.; Kübler, W.; Holland-Letz, T.; Giesel, F.L.; et al. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J. Nucl. Med. 2015, 56, 1697–1705.
  180. Banerjee, S.; Pillai, M.R.; Knapp, F.F. Lutetium-177 therapeutic radiopharmaceuticals: Linking chemistry, radiochemistry, and practical applications. Chem. Rev. 2015, 115, 2934–2974.
  181. Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 2009, 361, 123–134.
  182. Menear, K.A.; Adcock, C.; Boulter, R.; Cockcroft, X.L.; Copsey, L.; Cranston, A.; Dillon, K.J.; Drzewiecki, J.; Garman, S.; Gomez, S.; et al. 4--2H-phthalazin-1-one: A novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem. 2008, 51, 6581–6591.
  183. Slade, D. PARP and PARG inhibitors in cancer treatment. Genes Dev. 2020, 34, 360–394.
  184. D’Andrea, A.D. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair 2018, 71, 172–176.
  185. Ray Chaudhuri, A.; Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 2017, 18, 610–621.
  186. Pommier, Y.; O’Connor, M.J.; de Bono, J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci. Transl. Med. 2016, 8, 362ps317.
  187. Topatana, W.; Juengpanich, S.; Li, S.; Cao, J.; Hu, J.; Lee, J.; Suliyanto, K.; Ma, D.; Zhang, B.; Chen, M.; et al. Advances in synthetic lethality for cancer therapy: Cellular mechanism and clinical translation. J. Hematol. Oncol. 2020, 13, 118.
  188. Lowrance, W.; Dreicer, R.; Jarrard, D.F.; Scarpato, K.R.; Kim, S.K.; Kirkby, E.; Buckley, D.I.; Griffin, J.C.; Cookson, M.S. Updates to Advanced Prostate Cancer: AUA/SUO Guideline (2023). J. Urol. 2023, 209, 1082–1090.
  189. Hussain, M.; Daignault-Newton, S.; Twardowski, P.W.; Albany, C.; Stein, M.N.; Kunju, L.P.; Siddiqui, J.; Wu, Y.M.; Robinson, D.; Lonigro, R.J.; et al. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results from NCI 9012. J. Clin. Oncol. 2018, 36, 991–999.
  190. Hopkins, T.A.; Shi, Y.; Rodriguez, L.E.; Solomon, L.R.; Donawho, C.K.; DiGiammarino, E.L.; Panchal, S.C.; Wilsbacher, J.L.; Gao, W.; Olson, A.M.; et al. Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors. Mol. Cancer Res. MCR 2015, 13, 1465–1477.
  191. Zhang, T.; George, D.J.; Armstrong, A.J. Precision Medicine Approaches When Prostate Cancer Akts Up. Clin. Cancer Res. 2019, 25, 901–903.
  192. Blake, J.F.; Xu, R.; Bencsik, J.R.; Xiao, D.; Kallan, N.C.; Schlachter, S.; Mitchell, I.S.; Spencer, K.L.; Banka, A.L.; Wallace, E.M.; et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J. Med. Chem. 2012, 55, 8110–8127.
  193. Sweeney, C.; Bracarda, S.; Sternberg, C.N.; Chi, K.N.; Olmos, D.; Sandhu, S.; Massard, C.; Matsubara, N.; Alekseev, B.; Parnis, F.; et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): A multicentre, randomised, double-blind, phase 3 trial. Lancet 2021, 398, 131–142.
  194. de Bono, J.S.; Bracarda, S.; Sternberg, C.N.; Chi, K.N.; Olmos, D.; Sandhu, S.; Massard, C.; Matsubara, N.; Alekseev, B.; Gafanov, R.; et al. LBA4 IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Ann. Oncol. 2020, 31, S1153–S1154.
  195. ClinicalTrials.gov. Home Page. Available online: https://clinicaltrials.gov/study/NCT05348577 (accessed on 17 October 2023).
  196. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264.
  197. Mahoney, K.M.; Rennert, P.D.; Freeman, G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 2015, 14, 561–584.
  198. Agata, Y.; Kawasaki, A.; Nishimura, H.; Ishida, Y.; Tsubata, T.; Yagita, H.; Honjo, T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 1996, 8, 765–772.
  199. Rescigno, P.; de Bono, J.S. Immunotherapy for lethal prostate cancer. Nat. Rev. Urol. 2019, 16, 69–70.
  200. He, Y.; Wang, L.; Wei, T.; Xiao, Y.T.; Sheng, H.; Su, H.; Hollern, D.P.; Zhang, X.; Ma, J.; Wen, S.; et al. FOXA1 overexpression suppresses interferon signaling and immune response in cancer. J. Clin. Investig. 2021, 131, e147025.
  201. Boyiadzis, M.M.; Kirkwood, J.M.; Marshall, J.L.; Pritchard, C.C.; Azad, N.S.; Gulley, J.L. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J. Immunother. Cancer 2018, 6, 35.
  202. Taube, J.M.; Klein, A.; Brahmer, J.R.; Xu, H.; Pan, X.; Kim, J.H.; Chen, L.; Pardoll, D.M.; Topalian, S.L.; Anders, R.A. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 2014, 20, 5064–5074.
  203. Sfanos, K.S.; Bruno, T.C.; Meeker, A.K.; De Marzo, A.M.; Isaacs, W.B.; Drake, C.G. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009, 69, 1694–1703.
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