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.

Background. Gut colonization is a risk factor for infections with extended-spectrum beta-lactamase (ESBL)-producing organisms. We aimed to determine the ESBL class A reservoir among healthy individuals.Methods. We searched PubMed and EMBASE (through 10 July 2015) looking for studies that contained data for fecal colonization with ESBL class A bacteria among healthy individuals for each World Health Organization-defined region. Distribution of isolates among cefotaximase (CTX-M), sulfhydryl variable, and temoneira enzymes and data on previous antibiotic use, international travel, previous hospitalization, and animal contacts were extracted.Results. Sixty-six of 17 479 studies on 28 909 healthy individuals were included. The pooled prevalence of ESBL class A colonization was 14% (95% confidence interval [CI],9,20), with an increasing trend of 5.38% annually (P = .003). The pooled prevalence was higher in Asia and Africa (ranging from 46%, 95% CI, 29, 63 to 15%, 95% CI, 4, 31) and lower but still significant in central (3%, 95% CI, 1, 5), northern (4%, 95% CI, 2, 6), and southern Europe (6%, 95% CI, 1, 12) and the Americas (2%, 95% CI, 0, 5). CTX-Ms were the prevalent ESBL enzyme (69%). Antibiotic use for the prior 4 or 12 months was associated with a high colonization risk (risk ratio [RR] = 1.63; 95% CI, 1.19, 2.24 and RR = 1.58; 95% CI, 1.16, 2.16, respectively). International travel was also correlated with ESBL colonization [(RR = 4.06, (95% CI, 1.33, 12.41)].Conclusions. The ESBL colonization rate among healthy individuals is significant worldwide. This should be taken into consideration in infection control and antibiotic management decisions.

Cancers with dysfunctional mutations in BRCA1 or BRCA2, most commonly associated with some breast cancers, are deficient in the DNA damage repair pathway called homologous recombination (HR), which makes them exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib. This functional state and therapeutic sensitivity is referred to as “BRCAness”. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only a small proportion of prostate cancer (PCa) patients. We found that castration-resistant PCa (CRPC) cells increased expression of a set of HR-associated genes, including BRCA1, RAD54L and RMI2. Androgen-targeted therapy is typically not effective in CRPC patients. However, the androgen receptor (AR) inhibitor enzalutamide suppressed the expression of those HR genes, thus creating HR deficiency and BRCAness in CRPC cells. In a manner dependent on these gene expression effects, a “lead-in” treatment strategy, in which enzalutamide was followed by the combination of enzalutamide and olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of PCa cells in culture and suppressed the growth of PCa xenografts in mice. Thus, our study suggests that anti-androgen and PARP inhibitor combination therapy may be effective for patients with CRPC, and that pharmaceutically-induced BRCAness may expand the clinical use of PARP inhibitors.

Context To evaluate molecular mechanisms that play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer. Objective The understanding of mechanisms and biological pathways associated with the progression of prostate cancer under systemic androgen depletion or administration of novel anti-androgens abiraterone, enzalutamide and ARN-509. This review also examines the introduction of novel combinational approaches for patients with castrate resistant prostate cancer. Evidence Acquisition Pubmed was the data source and “castrate resistant prostate cancer”, “abiraterone, enzalutamide resistance mechanisms”, “resistance to androgen deprivation”, “AR mutations”, “amplifications”, “splice variants” and “AR alterations” were the keywords for the search. Papers published before 1990 were excluded from the review and only English papers were included. Evidence Synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of castrate resistant prostate cancer and the acquisition of resistance to novel anti-androgen axis agents. It focuses on androgen biosynthesis in the tumor microenvironment, AR alterations and post-transcriptional modifications, the role of glucocorticoid receptor, pathways of cellular stress and alternative oncogenic signaling which are de-repressed upon maximum AR inhibition promoting cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in prostate cancer are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses . Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with castrate resistant prostate cancer. Patient Summary In this review we looked for mechanisms related to the progression of prostate cancer in patients undergoing hormonal therapy and treatment with novel drugs targeting the androgen receptor. Based on recent data, the combination of maximal androgen receptor inhibition with novel agents targeting other tumor compensatory, non-AR related pathways may improve the survival and quality of life of patients with castrate-resistant prostate cancer (CRPC).

Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa), but most patients ultimately develop castration-resistance. We show here that MYB is transcriptionally activated by androgen deprivation or impairment of androgen receptor (AR) signaling. MYB gene silencing significantly inhibited PCa growth in vitro and in vivo. Microarray data revealed that c-Myb shares a substantial subset of DNA damage response (DDR) target genes with AR, suggesting that c-Myb may replace AR for the dominant role in the regulation of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures comprising AR, MYB, and their common DDR target genes are significantly correlated with metastasis, castration-resistance, recurrence, and shorter overall survival in PCa patients. We demonstrated in vitro that silencing of MYB, BRCA1 or TOPBP1 synergized with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) to increase cytotoxicity to PCa cells. We further demonstrated that targeting the c-Myb-TopBP1-ATR-Chk1 pathway by using the Chk1 inhibitor AZD7762 synergizes with OLA to increase PCa cytotoxicity. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the c-Myb-TopBP1-ATR-Chk1 pathway.

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The enhancer of zeste homolog 2 (EZH2), one of the polycomb-group proteins, is the catalytic subunit of Polycomb-repressive complex 2 (PRC2) and induces the trimethylation of the histone H3 lysine 27 (H3K27me3) promoting epigenetic gene silencing. EZH2 contains a SET domain promoting the methyltransferase activity, while the three other protein components of PRC2, namely EED, SUZ12, and RpAp46/48, induce compaction of the chromatin permitting EZH2 enzymatic activity. Numerous studies highlight the role of this evolutionary conserved protein as a master regulator of differentiation in humans involved in the repression of the homeotic gene and the inactivation of X-chromosome. Through its effects in the epigenetic regulation of critical genes, EZH2 has been strongly linked to cell cycle progression, stem cell pluripotency, and cancer biology, being currently at the cutting edge of research. Most recently, EZH2 has been associated with hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis. Several studies have evaluated the role of EZH2 in the regulation of T cell differentiation and plasticity as well as its implications in the development of autoimmune diseases and graft-versus-host disease (GVHD). The aim of this review is to summarize the current knowledge regarding the role of EZH2 in the regulation of the differentiation and function of T cells focusing on possible applications in various immune-mediated conditions, including autoimmune disorders and GVHD.